N2 -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof

ABSTRACT

N 2  -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof have been found to be effective as pharmaceutical agents for the inhibition and suppression of thrombosis in mammals.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of the followingapplications:

Ser. No. 653,217 of Jan. 28, 1976

Ser. No. 713,486 of Aug. 11, 1976

Ser. No. 671,568 of Mar. 29, 1976

Ser. No. 703,704 of July 8, 1976

The Ser. No. 671,568 is a divisional of Ser. No. 622,390 filed Oct. 14,1975, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to the discovery of certain new and useful N²-arylsulfonyl-L-argininamides and the pharmaceutically acceptable saltsthereof, which are of especial value in view of their outstandingantithrombotic properties and low toxicities.

2. Description of the Prior Art

In the past, there have been many attempts to obtain new and improvedagents for the treatment of thrombosis. The N²-(p-tolysulfonyl)-L-arginine esters have been found to be one type ofagent which can be used and these have been found to be effective indissolving blood clots. (U.S. Pat. No. 3,622,615, issued Nov. 23, 1971).One family of compounds which have been found to be particularly usefulas highly specific inhibitors of thrombin for the control of thrombosisis the N² -dansyl-L-arginine ester or amide. (Our pending U.S.application Ser. No. 496,939, filed Aug. 13, 1974 now U.S. Pat. No.3,978,045). However, there is a continuing need for a highly specificinhibitor of thrombin for the control of thrombosis, which exhibitslower toxicity.

SUMMARY OF THE INVENTION

It has now been discovered that N² -arylsulfonyl-L-argininamides exhibitantithrombotic activity and even lower toxicity levels at the samerelative potencies, as compared with the N² -dansyl-L-arginine ester oramide.

An N² -arylsulfonyl-L-argininamide having the formula (I): ##STR1## or apharmaceutically acceptable salt thereof, wherein R is ##STR2## WHEREINR₁ is --COOR₃ wherein R₃ is hydrogen, C₁ - C₁₀ alkyl, C₆ - C₁₀ aryl,C₇ - C₁₂ aralkyl or 5-indanyl; each R₂ independently is hydrogen, C₁ -C₁₀ alkyl, phenyl, C₁ - C₅ alkoxy, C₂ - C₆ alkoxycarbonyl or carboxywith the proviso that when n is 1, R₂ is not hydrogen or C₁ - C₁₀ alkyl;n is an integer of 1 to 4, R₁ is substituted into the piperidine ring atthe 2 or 3-position; and R₂ is substituted into the piperidine ring atthe 2, 3, 4, 5 or 6-position; and Ar is 5, 6, 7, 8-tetrahydronaphthyl ornaphthyl each of which is optionally substituted with at least onesubstituent selected from the group consisting of halo, hydroxy, nitro,cyano and C₁ - C₁₀ alkyl.

Also encompassed within this invention are pharmaceutically acceptablesalts thereof.

This invention also relates to a method for inhibiting activity andsuppressing activation of thrombin in vivo in mammals which comprisesadministering to a mammal apharmaceutically(antithrombotically)effective amount of an N²-arylnaphthalenesulfonyl-L-argininamide or the pharmaceuticallyacceptable salts thereof.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

This invention relates to a group of N² -arylsulfonyl-L-argininamides ofthe formula (I): ##STR3## wherein R is selected from the groupconsisting of ##STR4## wherein R₁ is selected from the group consistingof C₂ - C₁₀ alkyl, such as ethyl, propyl, butyl, isobutyl, pentyl,hexyl, octyl, decyl or the like, alkenyl of 3-10 (preferably 3-6) carbonatoms, such as allyl, 2-butenyl, 3-butenyl, 2-pentenyl or the like,alkynyl of 3-10 (preferably 3-6) carbon atoms, such as 2-propynyl,2-butynyl, 3-butynyl or the like, alkoxyalkyl of 2-10 (preferably 2-6)carbon atoms, such as methoxymethyl, ethoxymethyl, propoxymethyl,2-methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl, 2-methoxypropyl,3-methoxypropyl, 3-ethoxypropyl, 3-propoxypropyl, 4-methoxybutyl,4-ethoxybutyl, 4-butoxybutyl, 5-butoxypentyl or the like, alkylthioalkylof 2-10 (preferably 2-6) carbon atoms, such as methylthiomethyl,ethylthiomethyl, propylthiomethyl, 2-methylthioethyl, 2-ethylthioethyl,2-propylthioethyl, 3-methylthiopropyl, 2-methylthiopropyl,3-ethylthiopropyl, 3-proplthiopropyl, 4-methylthiobutyl,4-ethylthiobutyl, 4-butylthiobutyl, 5-butylthiopentyl or the like,alkylsulfinylalkyl of 2-10 (preferably 2-6) carbon atoms, such asmethylsulfinylmethyl, ethylsulfinylmethyl, propylsulfinylmethyl,2-methylsulfinylethyl, 2-ethylsulfinylethyl, 2-propylsulfinylethyl,3-methylsulfinylpropyl, 3-ethylsulfinylpropyl or the like. hydroxyalkylof 1-10 (preferably 1-6) carbon atoms, such as hydroxymethyl,2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl,3-hydroxybutyl, 5-hydroxypentyl or the like, carboxyalkyl of 2-10(preferably 2-7) carbon atoms, such as carboxymethyl, 2-carboxyethyl,2-carboxypropyl, 3-carboxypropyl, 1-carboxybutyl, 2-carboxybutyl,4-carboxybutyl or the like, alkoxycarbonylalkyl of 3-10 (preferably 3-8)carbon atoms, such as methoxycarbonylmethyl, 2-ethoxycarbonylethyl,2-ethoxycarbonylpropyl, 3-methoxycarbonylpropyl, 1-methoxycarbonylbutyl,2-ethoxycarbonylbutyl, 4-methoxycarbonylbutyl or the like,alkylcarbonylalkyl of 3 to 10 carbon atoms such as methylcarbonylethylor the like, haloalkyl of 1-10 (preferably 1-5) carbon atoms such aschloromethyl, 2-chloroethyl, 2-bromoethyl, 2-chloropropyl,3-chloropropyl, 2-chlorobutyl, 4-chlorobutyl or the like, aralkyl of7-15 (preferably 7-10) carbon atoms, such as benzyl, phenethyl,3-phenylpropyl, 4-phenylbutyl, 6-phenylhexyl, 1-phenylethyl,2-phenylpropyl or the like, -carboxyaralkyl of 8-15 (preferably 8-12)carbon atoms, such as -carboxybenzyl, -carboxyphenethyl or the like,C₃ - C₁₀ cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, C₄ - C₁₀cycloalkylalkyl, such as cyclopropylmethyl, cyclopentylmethyl,cyclohexylmethyl, 2-cyclohexylethyl, cyclooctylmethyl or the like,furfuryl, tetrahydrofurfuryl, optionally substituted with one or moreC₁ - C₅ alkyl, such as methyl, ethyl, propyl, butyl, or the like, and/orC₁ - C₅ alkoxy groups, such as methoxy, ethoxy, propoxy, butoxy or thelike, 3-furylmethyl, tetrahydro-3-furylmethyl, optionally substitutedwith one or more C₁ - C₅ alkyl such as methyl, ethyl, propyl, butyl orthe like, and/or C₁ - C₅ alkoxy groups, such as methoxy, ethoxy,propoxy, butoxy or the like, tetrahydro-2(3 or 4)-pyranylmethyloptionally substituted with one or more C₁ - C₅ alkyl such as methyl,ethyl, propyl, butyl or the like, and/or C₁ - C₅ alkoxy groups, such asmethoxy, ethoxy, propoxy, butoxy or the like1,4-dioxa-2-cyclohexylmethyl optionally substituted with one or moreC₁ - C₅ alkyl such as methyl, ethyl, propyl, butyl or the like, and/orC₁ - C₅ alkoxy groups, such as methoxy, ethoxy, propoxy, butoxy or thelike, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl, optionally substitutedwith one or more C₁ - C₅ alkyl such as methyl, ethyl, propyl, butyl orthe like, and/or C₁ - C₅ alkoxy groups such as methoxy, ethoxy, propoxybutoxy or the like and tetrahydro-3-thenyl; R₂ is selected from thegroup consisting of hydrogen, C₁ - C₁₀ alkyl, such as methyl, ethyl,propyl, butyl, tert-butyl, hexyl, octyl, decyl or the like, C₆ - C₁₀aryl, such as phenyl, m-tolyl, naphthyl or the like, aralkyl of 7-12(preferably 7-10) carbon atoms, such as benzyl, phenethyl or the like,or 5-indanyl; and n is an integer of 1, 2 or 3, ##STR5## wherein R₃ isselected from the group consisting of hydrogen, C₁ - C₁₀ alkyl, such asmethyl, ethyl, propyl, butyl, isobutyl, pentyl, hexyl, octyl, decyl orthe like, alkenyl of 3-10 (preferably 3-6) carbon atoms, such as allyl,2-butenyl, 3-butenyl, 2-pentenyl or the like, alkynyl of 3-10(preferably 3-6) carbon atoms, such as 2-propynyl, 2-butynyl, 3-butynylor the like, alkoxyalkyl of 2-10 (preferably 2-6) carbon atoms, such asmethoxymethyl, ethoxymethyl, propoxymethyl, 2-methoxyethyl,2-ethoxyethyl, 2-propoxyethyl, 2-methoxypropyl, 3-methoxypropyl,3-ethoxypropyl, 3-propoxypropyl, 4-methoxybutyl, 4-ethoxybutyl,4-butoxybutyl, 5-butoxypentyl or the like, alkylthioalkyl of 2-10(preferably 2-6) carbon atoms, such as methylthiomethyl,ethylthiomethyl, propylthiomethyl, 2-methylthioethyl, 2-ethylthioethyl,2-propylthioethyl, 3-methylthiopropyl, 2-methylthiopropyl,3-ethylthiopropyl, 3-propylthiopropyl, 4-methylthiobutyl,4-ethylthiobutyl, 4-butylthiobutyl, 5-butylthiopentyl or the like,alkylsulfinylalkyl of 2-10 (preferably 2-6) carbon atoms, such asmethylsulfinylmethyl, ethylsulfinylmethyl, propylsulfinylmethyl,2-methylsulfinylethyl, 2-ethylsulfinylethyl, 2-propylsulfinylethyl,3-methylsulfinylpropyl, 3-ethylsulfinylpropyl or the like, hydroxyalkylof 1-10 (preferably 1-6) carbon atoms, such as hydroxymethyl,2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl,3-hydroxybutyl, 5-hydroxypentyl or the like, carboxyalkyl of 2-10(preferably 2-7) carboxymethyl, 2-carboxyethyl, 2-carboxypropyl,3-carboxypropyl, 1-carboxybutyl, 2-carboxybutyl, 4-carboxybutyl or thelike, alkoxycarbonylalkyl of 3-10 (preferably 3-8) carbon atoms, such asmethoxycarbonylmethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylpropyl,3-methoxycarbonylpropyl, 1-methoxycarbonylbutyl, 2-ethoxycarbonylbutyl,4-methoxycarbonylbutyl or the like, alkylcarbonylalkyl of 3 to 10 carbonatoms such as methylcarbonylethyl or the like, haloalkyl or 1-10(preferably 1-5) carbon atoms such as chloromethyl, 2-chloroethyl,2-bromeoethyl, 2-chloropropyl, 3-chloropropyl, 2-chlorobutyl,4-chlorobutyl or the like, aralkyl of 7-15 (preferably 7-10) carbonatoms, such as benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl,6-phenylhexyl, 1-phenylethyl, 2-phenylpropyl or the like,α-carboxyaralkyl of 8-15 (preferably 8-12) carbon atoms, such asα-carboxybenzyl, α-carboxyphenethyl or the like, C₃ - C₁₀ cycloalkyl,such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl or cyclodecyl, C₄ - C₁₀ cycloalkylalkyl, such ascyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl,2-cyclohexylethyl, cyclooctylmethyl or the like, furfuryl,tetrahydrofurfuryl optionally substituted with one or more C₁ - C₅ alkylsuch as methyl, ethyl, propyl, butyl or the like, and/or C₁ - C₅ alkoxygroups, such as methoxy, ethoxy, propoxy, butoxy or the like3-furylmethyl, tetrahydro-3-furylmethyl optionally substituted with oneor more C₁ - C₅ alkyl such as methyl, ethyl, propyl, butyl or the like,and/or C₁ - C₅ alkoxy groups, such as methoxy, ethoxy, propoxy, butoxyor the like, tetrahydro-2 (3 or 5) -pyranylmethyl optionally substitutedwith one or more C₁ - C₅ alkyl such as methyl, ethyl, propyl, butyl orthe like, and/or C₁ - C₅ alkoxy groups, such as methoxy, ethoxy,propoxy, butoxy or the like, 1,4-dioxa-2-cyclohexylmethyl optionallysubstituted with one or more C₁ - C₅ alkyl such as methyl, ethyl,propyl, butyl or the like and/or C₁ - C₅ alkoxy groups, such as methoxy,ethoxy, propoxy, butoxy or the like, 2-thenyl, 3-thenyl,tetrahydro-2-thenyl optionally substituted with one or more C₁ - C₅alkyl such as methyl, ethyl, propyl, butyl or the like, and/or C₁ - C₅alkoxy groups, such as methoxy, ethoxy, propoxy, butoxy or the like, andtetrahydro-3-thenyl; R₄ is selected from the group consisting of alkylof 1-10 (preferably 1-5) carbon atoms, such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, pentyl or the like, carboxy,alkoxycarbonyl of 2-10 (preferably 2-5) carbon atoms, such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or the like, phenyloptionally substituted with one or more C₁ - C₅ alkyl, such as methyl,ethyl, propyl, butyl or the like, and/or C₁ - C₅ alkoxy groups, such asmethoxy, ethoxy, propoxy, butoxy or the like, aralkyl of 7-12(preferably 7-10) carbon atoms, such as benzyl, phenethyl or the like,and ring substituted benzyl wherein said substituent is alkyl of 1-5(preferably 1-3) carbon atoms, such as methyl, ethyl, propyl orisopropyl, or alkoxy of 1-5 (preferably 1-3) carbon atoms, such asmethoxy, ethoxy, propoxy or isopropoxy; R₅ is selected from the groupconsisting of hydrogen, C₁ - C₁₀ alkyl, such as methyl, ethyl, propyl,butyl, tert-butyl, hexyl, octyl, decyl or the like, C₆ - C₁₀ aryl, suchas phenyl, m-tolyl, naphthyl or the like, aralkyl of 7-12 (preferably7-10) carbon atoms, such as benzyl, phenethyl or the like, and5-indanyl; and m is an integer of 0, 1 or 2, ##STR6## wherein R₆ is--COOR₈ wherein R₈ is selected from the group consisting of hydrogen,C₁ - C₁₀ alkyl, such as methyl, ethyl, propyl, butyl, tertbutyl, hexyl,octyl, decyl or the like, C₆ - C₁₀ aryl, such as phenyl, m-tolyl,naphthyl or the like, aralkyl of 7-12 (preferably 7-10) carbon atoms,such as benzyl, phenethyl or the like, and 5-indanyl; each R₇independently is hydrogen, alkyl of 1-10 (preferably 1-6)carbon atoms,such as methyl, ethyl, propyl, isopropyl, butyl, hexyl, octyl, decyl orthe like, phenyl, C₁ - C₅ alkoxy, such as methoxy, ethoxy, propoxy,butoxy or the like, C₂ - C₆ alkoxycarbonyl, such as methoxycarbonyl,ethoxycarbonyl or the like, or carboxy; p is an integer of 1 to 4; R₆ issubstituted at the 2 or 3-position; and R₇ can be substituted at the 2,3, 4, 5 or 6 -position, ##STR7## optionally substituted with one or moreC₁ - C₅ alkyl, such as methyl, ethyl, propyl, butyl or the like, or C₁ -C₅ alkoxy groups, such as methoxy, ethoxy, propoxy, butoxy or the likewherein R₉ is selected from the group consisting of hydrogen, C₁ - C₁₀alkyl, such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl,decyl or the like, C₆ - C₁₀ aryl, such as phenyl, m-tolyl, napthyl orthe like, aralkyl of 7-12 (preferably 7-10) carbon atoms, such asbenzyl, phenethyl or the like, and 5-indanyl; and r is an integer of 1,2, 3 or 4, ##STR8## wherein R₁₀ is selected from the group consisting ofhydrogen, C₁ - C₁₀ alkyl, such as methyl, ethyl, propyl, butyl,tert-butyl, hexyl, octyl, decyl or the like, C₆ - C₁₀ aryl, such asphenyl, m-tolyl, naphthyl or the like, aralkyl of 7-12 (preferably 7-10)carbon atoms, such as benzyl, phenethyl or the like, and 5-indanyl; Z isselected from the group consisting of oxy (--O--), thio (--S--) andsulfinyl (--SO--); q is an integer of 0 or 1, and ##STR9## wherein R₁₁is selected from the group consisting of hydrogen, C₁ - C₁₀ alkyl, suchas methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, decyl or thelike, C₆ - C₁₀ aryl, such as phenyl, m-tolyl, naphthyl or the like,aralkyl of 7-12 (preferably 7-10) carbon atoms, such as benzyl,phenethyl or the like, and 5-indanyl; i is an integer of 0, 1 or 2; j isan integer of 0, 1 or 2; and the sum of i + j is an integer of 1 or 2;and Ar is a phenyl, naphthyl, naphthoquinonyl, anthryl, phenanthryl,pentalenyl, heptalenyl, azulenyl, biphenylenyl, as -indacenyl,S-indacenyl, acenaphthylenyl, phenylcarbonylphenyl, phenoxyphenyl,benzofuranyl, isobenzofuranyl, benzo b! thienyl, isobenzothienyl,oxanthrenyl, thianthrenyl, dibenzofuranyl, dibenzothienyl,phenoxathiinyl, indolyl, 1H,indazolyl, quinolyl, isoquinolyl,phthalazinyl, 1, 8-naphthyridinyl, quinoxalinyl, quinazolinyl,cinnolinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl,phenoxazinyl or benzimidazolyl group each of which is unsubstituted orsubstituted with one or more groups selected from the group consistingof halo, nitro, cyano, hydroxy, alkyl of 1-10 (preferably 1-5) carbonatoms, such as methyl, ethyl, propyl, butyl or the like, alkoxy of 1-10(preferably 1-5) carbon atoms, such as methoxy, ethoxy, propoxy, butoxyor the like, dialkylamino of 2-20 (preferably 2-10) carbon atoms, suchas dimethylamino, diethylamino, dipropylamino or the like, sulfoamino,carbamoyl, N, N-dialkylcarbamoyl of 3-10 (preferably 3-7) carbon atoms,such as N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl or the like,amono, alkylamino of 1-10 (preferably 1-5) carbon atoms, such asmethylamino, ethylamino, propylamino, butylamino or the like, mercapto,alkylthio of 1-10 (preferably 1-5) carbon atoms, such as methylthio,ethylthio, propylthio, butylthio or the like, aralkyl of 7-12(preferably 7-10) carbon atoms, such as benzyl, phenethyl or the like,carboxyl, alkoxycarbonyl of 2-10 (preferably 2-6) carbon atoms, such asmethoxycarbonyl, ethoxycarbonyl or the like, carboxyalkyl of 2-10(preferably 2-6) carbon atoms, such as carboxymethyl, 2-carboxyethyl,2-carboxypropyl or the like, acylamino such as alkylcarbonylamino of1-10 (preferably 1-5) carbon atoms, such as acetylamino, propionylaminoor the like, alkylcarbonyl of 2-10 (preferably 2-6) carbon atoms, suchas acetyl, propionyl or the like, hydroxyalkyl of 1-10 (preferably 1-5)carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl orthe like, haloalkyl of 1-10 (preferably 1-5) carbon atoms, such aschloromethyl, trifluoromethyl, bromomethyl, 2-chloroethyl or the like,and phenyl optionally substituted with at least one hydroxy and/or C₁ -C₅ alkoxy, such as methoxy, ethoxy, propoxy, butoxy or the like;

or a 5, 6, 7, 8-tetrahydronaphthyl, C₇ - C₁₂ aralkyl, 9,10-dihydroanthryl, 5, 6, 7, 8-tetrahydroanthryl, 9,10-dihydrophenanthryl, 1, 2, 3, 4, 5, 6, 7, 8-octahydrophenanthryl,indenyl, indanyl, fluorenyl, acenaphthenyl, phenylthiophenyl, 1,2-ethylenedioxyphenyl, chromanyl, isochromanyl, 2,3-dihydrobenzofuranyl, 1, 3-dihydroisobenzofuranyl, 2,3-ethylenedioxynaphthyl, xanthenyl, thioxanthenyl, 1,2-trimethylenedioxyphenyl, 2H-chromenyl, 3, 4-dehydro-1-isochromanyl,4H-chromenyl, indolinyl, isoindolinyl, 1, 2, 3, 4-tetrahydroquinolyl, or1, 2, 3, 4-tetrahydroisoquinolyl groups each of which is unsubstitutedwith one or more groups selected from the group consisting of halo,nitro, cyano, hydroxy, alkyl of 1-10 (preferably 1-5) carbon atoms, suchas methyl, ethyl, propyl, butyl or the like, alkoxy of 1-10 (preferably1-5) carbon atoms, such as methoxy, ethoxy, propoxy, butoxy or the like,dialkylamino of 2-20 (preferably 2-10) carbon atoms, such asdimethylamino, diethylamino, dipropylamino or the like, sulfoamino,carbamoyl, N, N-dialkylcarbamoyl of 3-10 (preferably 3-7) carbon atoms,such as N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl or the like,amino, alkylamino of 1-10 (preferably 1-5) carbon atoms, such asmethylamino, or the like, mercapto, alkylthio of 1-10 (preferably 1-5)carbon atoms, such as methylthio, ethylthio, propylthio, butylthio orthe like, aralkyl of 7-12 (preferably 7-10) carbon atoms, such asbenzyl, phenethyl or the like, carboxyl, alkoxycarbonyl of 2-10(preferably 2-6) carbon atoms, such as methoxycarbonyl, ethoxycarbonylor the like, carboxyalkyl of 2-10 (preferably 2-6) carbon atoms, such ascarboxymethyl, 2-carboxyethyl, 2-carboxypropyl or the like, acylaminosuch as alkylcarbonylamino of 1-10 (preferably 1-5) carbon atoms, suchas acetylamino, propionylamino or the like, alkylcarbonyl of 2-10(preferably 2-6) carbon atoms, such as acetyl, propionyl, or the like,hydroxyalkyl or 1-10 (preferably 1-5) carbon atoms, such ashydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl or the like, haloalkyl of1-10 (preferably 1-5) carbon atoms, such as chloromethyl,trifluoromethyl, bromomethyl, 2-chloroethyl or the like, oxo and phenyloptionally substituted with at least one hydroxy and/or C₁ - C₅ alkoxy,such as methoxy, ethoxy, propoxy, butoxy or the like.

Illustrative of suitable N² -arylsulfonyl-L-argininamides are thoseshown in the table below. In this table, the prior art reference citedin the second column discloses a method of preparation for the compoundlisted in the second column. The Example No listed in the last columnrefers to an Example of this application which discloses the details ofa method by which the product compound of the fifth column of the tablemay be prepared.

    TABLE I        Product  or salt thereofArSO.sub.2 Cl or ArSO.sub.3 H Starting     material      ##STR10##       Preparation NO. (Literature reference) Amino acid ester Ar R Procedure             1      ##STR11##      ##STR12##      ##STR13##      ##STR14##      1  Ger. 1,123,315      2     ##STR15##      ##STR16##      ##STR17##      ##STR18##      1  Ger. 1,123,315      3     ##STR19##      ##STR20##      ##STR21##      ##STR22##      2  Ber. 54,102 (1921)      4     ##STR23##      ##STR24##      ##STR25##      ##STR26##      3  CA 23, 1897      5     ##STR27##      ##STR28##      ##STR29##      ##STR30##      2  CA 25, 5420      6     ##STR31##      ##STR32##      ##STR33##      ##STR34##      2  CA 22,413      7     ##STR35##      ##STR36##      ##STR37##      ##STR38##      2  J. Ger. Chem. 6,444(1936)      8     ##STR39##      ##STR40##      ##STR41##      ##STR42##      1  Compt. rend 218,973(1944)      9     ##STR43##      ##STR44##      ##STR45##      ##STR46##      2  CA 33 4227      10     ##STR47##      ##STR48##      ##STR49##      ##STR50##      2  Can. J. Chem 41,100(1963) 11      ##STR51##      ##STR52##      ##STR53##      ##STR54##      1  Compt. rend 218,973(1944)      12     ##STR55##      ##STR56##      ##STR57##      ##STR58##      2  CA 49,5414      13     ##STR59##      ##STR60##      ##STR61##      ##STR62##      1  Naturwisserschaften 49,57(1962)      14     ##STR63##      ##STR64##      ##STR65##      ##STR66##      1  Z. Chem. 3,426(1963)      15     ##STR67##      ##STR68##      ##STR69##      ##STR70##      1  Z. Chem. 3,426(1963)      16     ##STR71##      ##STR72##      ##STR73##      ##STR74##      1  Ger. 1,219,477      17     ##STR75##      ##STR76##      ##STR77##      ##STR78##      1  Kogyo. Kaga Ku. Zashi 62,703(1969)      18     ##STR79##      ##STR80##      ##STR81##      ##STR82##      1  J. Chem. Soc. 1970,2500      19     ##STR83##      ##STR84##      ##STR85##      ##STR86##      1  Ber 31,1663      20     ##STR87##      ##STR88##      ##STR89##      ##STR90##      1  Ber 26,906      21     ##STR91##      ##STR92##      ##STR93##      ##STR94##      1  Beilstein 11I,135      22     ##STR95##      ##STR96##      ##STR97##      ##STR98##      3  mp 88-9°      23     ##STR99##      ##STR100##      ##STR101##      ##STR102##      3  mp 80-2      24     ##STR103##      ##STR104##      ##STR105##      ##STR106##      3  mp 55°      25     ##STR107##      ##STR108##      ##STR109##      ##STR110##      1  Ger 56780 (CA,68,12704u)      26     ##STR111##      ##STR112##      ##STR113##      ##STR114##      3  Helv. chim. Acta 46,727(1963)      27     ##STR115##      ##STR116##      ##STR117##      ##STR118##      2  Zhur Obehchei Khim 18,1459(1948)      28     ##STR119##      ##STR120##      ##STR121##      ##STR122##      2  Per 84,1254(1956)      29     ##STR123##      ##STR124##      ##STR125##      ##STR126##      1  CA. 47,10519      30     ##STR127##      ##STR128##      ##STR129##      ##STR130##      1  CA. 32,2938      31     ##STR131##      ##STR132##      ##STR133##      ##STR134##      1  Monatsh. 92,677(1961)      32     ##STR135##      ##STR136##      ##STR137##      ##STR138##      2  Compt. rend 198,2260(1934)      33     ##STR139##      ##STR140##      ##STR141##      ##STR142##      2  Compt. rend 198,2260(1934)      34     ##STR143##      ##STR144##      ##STR145##      ##STR146##      1  J. Am. Chem. Soc 58,717(1936)      35     ##STR147##      ##STR148##      ##STR149##      ##STR150##      3  Montash. 85,235(1954)      36     ##STR151##      ##STR152##      ##STR153##      ##STR154##      2  J. Chem. Eng. Data 12,610(1967)      37     ##STR155##      ##STR156##      ##STR157##      ##STR158##      2  J. Ger. Chem. 10,1077(1940) 38      ##STR159##      ##STR160##      ##STR161##      ##STR162##      2  J. Pharm. Soc. Japan 73,1878(1953)      39     ##STR163##      ##STR164##      ##STR165##      ##STR166##      2  J. Pharm. Soc. Japan 76,103(1958) 40      ##STR167##      ##STR168##      ##STR169##      ##STR170##      1  J. Chem. Soc 1958,3830 41      ##STR171##      ##STR172##      ##STR173##      ##STR174##      2  J. Chem. Soc 1958, 1499 42      ##STR175##      ##STR176##      ##STR177##      ##STR178##      2 43      ##STR179##      ##STR180##      ##STR181##      ##STR182##      1  J. Chem Soc 1968, 687 44      ##STR183##      ##STR184##      ##STR185##      ##STR186##      1  J. Chem. Soc 1968,687      45     ##STR187##      ##STR188##      ##STR189##      ##STR190##      1  J. Chem. Soc 1968, 687      46     ##STR191##      ##STR192##      ##STR193##      ##STR194##      1  J. Chem. Soc. 1968, 687      47     ##STR195##      ##STR196##      ##STR197##      ##STR198##      3  J. Chem. Soc. 72, 4890(1950)      48     ##STR199##      ##STR200##      ##STR201##      ##STR202##      2  U.S. Pat. No. 2,476,541      49     ##STR203##      ##STR204##      ##STR205##      ##STR206##      2  Zhur Obschei Khim 23,842      50     ##STR207##      ##STR208##      ##STR209##      ##STR210##      2  Zhur Obschei Khim 23,842      51     ##STR211##      ##STR212##      ##STR213##      ##STR214##      2  J. Am. Chem. Soc. 75,2095(1953)      52     ##STR215##      ##STR216##      ##STR217##      ##STR218##      2  Brit 590,645(1947)      53     ##STR219##      ##STR220##      ##STR221##      ##STR222##      2  J. Org. Chem. 23,435(1958)      54     ##STR223##      ##STR224##      ##STR225##      ##STR226##      2  U.S. Pat. No. 2,708,669      55     ##STR227##      ##STR228##      ##STR229##      ##STR230##      2  Gazz. Chim. ital. 81,764(1959)      56     ##STR231##      ##STR232##      ##STR233##      ##STR234##      2  Pharm. Bull. (Japan) 5,297 (1954)      57     ##STR235##      ##STR236##      ##STR237##      ##STR238##      3  (Aldrich)      58     ##STR239##      ##STR240##      ##STR241##      ##STR242##      3  Pharmazie 20,549      59     ##STR243##      ##STR244##      ##STR245##      ##STR246##      2  J. Am. Chem. Soc. 71      60     ##STR247##      ##STR248##      ##STR249##      ##STR250##      1  U.S. Pat. No. 2,656,354      61     ##STR251##      ##STR252##      ##STR253##      ##STR254##      1Compt. Rend Acast & monatch Sci 18,243      62     ##STR255##      ##STR256##      ##STR257##      ##STR258##      2  J. pr  2!118, 75      63     ##STR259##      ##STR260##      ##STR261##      ##STR262##      2  Photophysik Photochem 58, 3 (1963)      64     ##STR263##      ##STR264##      ##STR265##      ##STR266##      2  J. Gen. Chem. 16, 1873      65     ##STR267##      ##STR268##      ##STR269##      ##STR270##      2  Ber., 86, 951 (1953)      66     ##STR271##      ##STR272##      ##STR273##      ##STR274##      2  Ber 86, 951 (1963)      67     ##STR275##      ##STR276##      ##STR277##      ##STR278##      2  Ber 86, 951 (1953) 68      ##STR279##      ##STR280##      ##STR281##      ##STR282##      2  Zhur Obschei Khim 30, 1218 (1960) 69      ##STR283##      ##STR284##      ##STR285##      ##STR286##      2  Zhur Obschei Khim 30, 1218 (1960)      70     ##STR287##      ##STR288##      ##STR289##      ##STR290##      2  Bull. Soc. Chem. France 1950, 466      71     ##STR291##      ##STR292##      ##STR293##      ##STR294##      2  Bull. Soc. Chem France 1950, 466      72     ##STR295##      ##STR296##      ##STR297##      ##STR298##      1  Zhur. Oschei Khim 22, 866 (1952)      73     ##STR299##      ##STR300##      ##STR301##      ##STR302##      2  Zhur Obschei Khim 22, 866 (1952)       74     ##STR303##      ##STR304##      ##STR305##      ##STR306##      2  Zhur. Obschei Khim 22, 866 (1952)      75     ##STR307##      ##STR308##      ##STR309##      ##STR310##      2  Zhur Obschei Khim 23, 866 (1952)      76     ##STR311##      ##STR312##      ##STR313##      ##STR314##      2  Roczniki chem 15, 965(1935)      77     ##STR315##      ##STR316##      ##STR317##      ##STR318##      2  CA 62, 14675G      78     ##STR319##      ##STR320##      ##STR321##      ##STR322##      2  CA 26 4723      79     ##STR323##      ##STR324##      ##STR325##      ##STR326##      2  Japanese Patent Published  39-26975      80     ##STR327##      ##STR328##      ##STR329##      ##STR330##      2  Japanese Patent Published  39-26975      81     ##STR331##      ##STR332##      ##STR333##      ##STR334##      2  J. Am. Chem. Soc. 57,1533(1935)      82     ##STR335##      ##STR336##      ##STR337##      ##STR338##      2  J. Am. Chem. Soc. 59,1533 (1935) 83      ##STR339##      ##STR340##      ##STR341##      ##STR342##      2  CA 45 90636      84     ##STR343##      ##STR344##      ##STR345##      ##STR346##      2  Org. Synth II. 539      85     ##STR347##      ##STR348##      ##STR349##      ##STR350##      3  (No. 8)      86 "     ##STR351##      ##STR352##      ##STR353##      2      87 "     ##STR354##      ##STR355##      ##STR356##      6 88 "      ##STR357##      ##STR358##      ##STR359##      6 89 "      ##STR360##      ##STR361##      ##STR362##      3

Also illustrative of suitable N² -arylsulfonyl-L-argininamides are thoseshown in the table below. In this table, the Example No listed in thesixth column refers to the Example of this application by which thecompound in the first column was prepared.

    Table 2       Compound Concentration    Sample      ##STR363##       required toprolong the coagulationtime by afactor of two process Prepar     ation m.p. Lower: Found (%)Upper: Calculated (%)Elementary analysis      I.R. (KBr) No. Ar R Addition moiety (μM) (Ex. No.) (° C) C H     N      (cm.sup.-1)                1      ##STR364##      ##STR365##      -- 8 1 powder 52.7652.68 6.35  6.21 13.3813.30 3,3603,1601,620 2 "      ##STR366##      1/2 H.sub.2      SO.sub.3  1 134-6 52.2552.07 6.826.73 11.2910.89     ##STR367##      3 "      ##STR368##      -- 0.31 powder 53.6253.48 6.566.43 13.0312.98 3,3603,1401,622 4 "      ##STR369##      1/2 H.sub.2      SO.sub.3  1 164-6 52.9852.69 7.006.98 11.0410.86 3,3903,1651,7351,370     5 "      ##STR370##      -- 2 1 powder 53.6253.43 6.566.51 13.0313.12 3,3603,1601,620 6 "      ##STR371##      1/2 H.sub.2                                                             1      SO.sub.3  1 " 52.9852.59 7.006.79 11.0410.89 3,3903,1701,737,370 7 "      ##STR372##      -- 5 1 " 54.4354.38 6.766.79 12.7012.56 3,3503,1801,630 8 "      ##STR373##      1/2 H.sub.2      SO.sub.3  1 195-6 53.6953.40 7.157.12 10.8010.56 3,3803,1801,7381,375     9 "      ##STR374##      -- 1.5 1 powder 55.2154.98 6.957.02 12.3812.47 3,3603,2001,622 10 "      ##STR375##      1/2 H.sub.2 SO.sub.3  1 198-200 54.37 54.30 7.307.27 10.5710.36     3,3603,1601,7301,368      11 "     ##STR376##      --  1 powder 56.6456.41 7.307.17 11.8011.51 3,3603,1801,620 12 "      ##STR377##      1/2 H.sub.2      SO.sub.3  1 172-174 55.6455.31 7.597.63 10.1410.18 3,3803,1801,7401,375      13 "     ##STR378##      - 0.5 3 powder 51.2050.93 6.176.02 12.9812.63 3,3803,1801,630 14 "      ##STR379##      ##STR380##      1.5 3 185 47.6747.64 4.924.81 11.1211.12 3.3753,200 1,740 15 "      ##STR381##      -- 2.5 3 powder 52.0752.21 6.376.04 12.6712.51 3,3803,2001,620 16 "      ##STR382##      --  3 " 53.6953.53 6.766.69 12.0412.38 3,3803,2001,740 17 "      ##STR383##      -- 2.5 1 " 52.9052.71 6.576.43 12.3412.46 3,3503,1601,640 18 "      ##STR384##      1/2 H.sub.2      SO.sub.3  1 " 52.4052.16 6.967.13 10.5410.28     ##STR385##      19 "      ##STR386##      -- 5 1 " 52.0751.91 6.376.19 12.6512.38 3,3603,1601,620 20 "      ##STR387##      1/2 H.sub.2      SO.sub.3  1 " 51.6851.43 6.826.66 10.7610.58     ##STR388##      21 "      ##STR389##      -- 4 1 " 52.9052.59 6.576.41 12.3412.16 3,3603,1601,640 22 "      ##STR390##      1/2 H.sub.2      SO.sub.3  1 powder 52.9852.73 7.007.00 11.0410.82     ##STR391##      23      ##STR392##      ##STR393##      -- 4 4 " 51.2051.31 6.176.01 12.9812.67 3,3603,1801,610 24 "      ##STR394##      ##STR395##       4 225-7 47.6747.62 4.924.84 11.1211.18 3,3753,2001,742 25 "      ##STR396##      -- 2 1 powder 53.6253.58 6.566.48 13.0312.94 3,3803,2001,630 26 "      ##STR397##      1/2 H.sub.2      SO.sub.3  1 224 52.9852.73 7.007.00 11.0410.82     ##STR398##      27      ##STR399##      ##STR400##      -- 15 1 powder 52.8952.77 6.576.80 12.3412.59 3,3803,2001,625 28 "      ##STR401##      1/2 H.sub.2      SO.sub.3  1 " 52.3952.10 6.976.84 10.5410.21     ##STR402##      29 "      ##STR403##      --  1 " 55.2055.00 6.956.81 12.3812.21 3,3603,1501,620 30 "      ##STR404##      1/2 H.sub.2                                                             1      SO.sub.3  1 " 54.3654.25 7.307.11 10.5710.81 3,3703,2001,735,370  31      ##STR405##      ##STR406##       -- 0.5 1 " 54.4354.21 6.556.50 13.8013.79 3,360 3,1801,632 32 "      ##STR407##      1/2 H.sub.2      SO.sub.3  1 " 53.6353.50 7.006.79 11.5811.40     ##STR408##      33 "      ##STR409##      --  1 " 51.8651.64 6.136.09 13.7513.84 3,3703,2001,625 34 "      ##STR410##      1/2 H.sub.2      SO.sub.3  1 " 55.2155.11 6.956.76 12.3812.27     ##STR411##      35     ##STR412##      ##STR413##       -- 0.5 3 " 51.8651.72 6.136.11 13.7513.63 3,3703,1601,620 36 "      ##STR414##      ##STR415##       3 158-160 47.9447.83 4.854.80 11.5111.43 3,3753,2001,740 37 "      ##STR416##      --  1 powder 53.5353.40 6.336.21 14.1914.04 3.3753,1501,620 38 "      ##STR417##      1/2 H.sub.2                                                             1      SO.sub.3  1 " 52.8652.77 6.836.66 11.8611.75 3,3803,2001,740,370 39 "      ##STR418##      -- 0.5 1 " 54.4354.22 6.556.31 13.8013.59 3,3803,1501,620 40 "      ##STR419##      1/2 H.sub.2 SO.sub.3  1 131-137(dec.) 53.6353.40 7.007.10 11.5811.40      ##STR420##      41 "      ##STR421##      --  1 powder 55.2655.21 6.766.65 13.4313.29 3,3501,630 42 "      ##STR422##      1/2 H.sub.2 SO.sub.3  1 169-175(dec.) 54.3554.27 7.177.00 11.3211.08      ##STR423##      43      ##STR424##      ##STR425##      -- 2.5 1 powder 51.8651.77 6.136.00 13.7513.72 3,3653,2001,620 44 "      ##STR426##      1/2 H.sub.2      SO.sub.3 1 " 51.4751.20 6.656.35 11.5411.24     ##STR427##      45 "      ##STR428##      --  1 " 54.4354.28 6.556.31 13.8013.70 3.3753,2001,622 46 "      ##STR429##      1/2 H.sub.2                                                             1      SO.sub.3  1 " 53.6353.53 7.007.08 11.5811.40 3,3803,2001,740,370 47 "      ##STR430##      --   1 " 52.7652.47 6.356.01 13.3813.09 3,3753,1801,620 48 "      ##STR431##      1/2 H.sub.2                                                             1      SO.sub.3  1 " 52.2452.00 6.826.55 11.2811.00 3,3803,2001,740,368 49      ##STR432##      ##STR433##      0.5H.sub.2 SO.sub.3  1 189-191(dec.) 55.6855.36 6.336.35 10.4710.45     3,3603,1601,730 50 "      ##STR434##      -- 2.5 1 powder 56.7356.43 5.825.80 12.2512.19 3,3703,2001,615 51 "      ##STR435##      ##STR436##       1 132-135(dec.) 52.7852.61 5.175.15 10.2610.23 3,3603,1801,720 52 "      ##STR437##      -- 10 1 powder 57.4257.19 6.026.10 11.9611.73 3,3603,1601,620 53 "      ##STR438##      ##STR439##       1 157-158(dec.) 52.7852.63 5.175.14 10.2610.09 3,3803,2201,750 54 "      ##STR440##      -- 3.0 1 powder 57.4257.09 6.026.06 11.9611.74 3,3603,2001,590 55 "      ##STR441##      ##STR442##       1 155-157(dec.) 53.2553.13 5.305.21 10.1110.03 3,3803,1801,720 56 "      ##STR443##      -- 50 1 powder 58.0857.93 6.22 6.04 11.6811.54 3,200-3,380(broad)1,620     57      ##STR444##      ##STR445##      ##STR446##       1 153-156(dec.) 52.2852.14 5.034.98 10.4110.36 3,4003,0801,740 58 "      ##STR447##      -- 6.5 1 powder 56.7356.58 5.825.73 12.2512.14 3,000-3,400(broad)1,600     59      ##STR448##      ##STR449##      ##STR450##       1 144-148(dec.) 53.6753.69 5.265.24 10.4310.39 3,3603,2001,720 60 "      ##STR451##      -- 50 1 powder 59.0459.14 6.196.15 12.3012.28  3,040-3,360(broad) 1,610     61 "      ##STR452##      ##STR453##       1 155-158(dec.) 53.1954.97 5.125.06 10.5910.48 3,4003,2001,730 62 "      ##STR454##      -- 15 1 powder 58.3758.19 6.005.98 12.6112.49 3,300 (broad)1,640 63      ##STR455##      ##STR456##      ##STR457##       1 147-150(dec.) 59.1959.23 5.125.07 10.59 10.54 3,4003,2301,750 64 "      ##STR458##      -- 20 1 powder 58.3758.21 6.005.93 12.6112.46 3,200 (broad)1,620 65      ##STR459##      ##STR460##      --  1 " 60.2960.21 6.586.56 11.7211.64 3,3653,1701,730 66 "      ##STR461##      -- 2.0 1 " 57.6657.48 5.77 5.74 12.9312.84 3,3603,1601,610 67      ##STR462##      ##STR463##      -- 1 1 " 50.2550.45 5.956.01 13.3213.15 3,3501,6201,3801,150 68      ##STR464##      ##STR465##      1/2 H.sub.2                                                             1      SO.sub.3  1 " 50.4350.57 6.656.58 10.5010.71 3,3501,7451,650,360 69 "      ##STR466##      -- 5 1 171-2 50.6050.51 6.196.30 12.2912.40 3,4001,6351,2601,160 70 "      ##STR467##      --  2 powder 55.4055.65 6.626.81 12.4312.19 3,2201,7501,640 71      ##STR468##      ##STR469##      -- 5 2 " 53.8253.66 6.215.96 13.0812.81  3,3501,6251,155 72      ##STR470##      ##STR471##      ##STR472##       2 192-193 49.5849.24 4.874.70 11.5611.85 3,2101,7471,638 73 "      ##STR473##      -- 3 2 powder 54.6456.88 6.186.31 13.8513.83 3,200 (broad)1,6201,150 74      ##STR474##      ##STR475##      -- 0.4 2 " 54.6354.50 6.426.09 12.7412.81 3,3701,6251,158 75      ##STR476##      ##STR477##      ##STR478##       2 188-190 50.1750.01 5.034.78 11.3811.56 3,2001,7401,635 76 "      ##STR479##      -- 0.15 2 powder 55.4755.49 6.406.33 13.9813.51 3,250 (broad)1,625 77      ##STR480##      ##STR481##      --  2 " 57.0256.81 6.816.91 12.7912.78 3,2001,7401,635 78 "      ##STR482##      --  2 powder 55.4755.31 6.406.68 13.4813.21  3,3501,6201,150 79      ##STR483##      ##STR484##      ##STR485##       2 222-3 49.8249.57 5.094.88 11.9911.68 3,2001,7451,630 80 "      ##STR486##      -- 0.35 2 powder 54.6354.55 6.426.42 12.7412.58 3,350 (broad)1,6201,150     81      ##STR487##      ##STR488##      ##STR489##       2 154-6 50.9251.28 5.375.21 10.6610.59 3,4001,7351,635 82 "      ##STR490##      --  2 powder 56.1356.11 6.806.85 12.1211.95 3,300 (broad)1,6101,255 83      ##STR491##      ##STR492##      ##STR493##       2 179-180 50.3850.34 5.235.18 10.8211.05 3,3801,7351,635 84 "      ##STR494##      --  2 powder 55.4055.71 6.626.48 12.4312.53 3,3601,620 1,150 85      ##STR495##      ##STR496##      ##STR497##       2 125(soften) 50.7350.58 5.185.11 11.1910.93 3,3801,7351,638 86 "      ##STR498##      --  2 powder 56.2656.41 6.616.48 13.1213.27 3,3601,6201,158 87      ##STR499##      ##STR500##      --  2 " 57.5057.56 7.157.08 11.5611.71 3,3302,9601,7401,640 88 "      ##STR501##      -- 0.5 2 " 56.1356.11 6.806.81 12.1211.963,4001,620 89 "      ##STR502##      --  2 " 57.5057.15 7.157.21 11.5611.62 3,3602,9601,735 90 "      ##STR503##      --  2 " 56.1356.21 6.806.81 12.1212.03 3,4001,6201,150 91 "      ##STR504##      --  2 " 54.6354.54 6.426.40 12.7412.68 3,3501,6201,150 92 "      ##STR505##      --  2 powder 56.1356.08 6.806.91 12.1212.08 3,2501,7401,640 93      ##STR506##      ##STR507##      --  2 " 57.0256.86 6.816.83 12.7912.68 3,2301,7401,650 94 "      ##STR508##      --  2 " 54.6354.59 6.426.38 12.7412.68 3,2501,6201,160 95      ##STR509##      ##STR510##      ##STR511##       2 161-163 48.9749.05 4.714.73 11.76 11.58 3,3401,7381,635 96 "      ##STR512##      --  2 powder 53.8253.68 6.216.08 13.0812.85 3,3701,6351,2551,155 97      ##STR513##      ##STR514##      --  2 " 54.6454.58 6.186.09 13.8513.93 3,3701,6401,2601,155 98      ##STR515##      ##STR516##      ##STR517##       1 165-168(dec.) 51.9451.50 5.645.41 10.3410.10 3,3903,220 1,740 99 "      ##STR518##       --  1 powder 56.1356.00 6.816.73 12.1212.01 3,350 (broad)1,640 100 "      ##STR519##      ##STR520##       1 178-181(dec.) 51.9452.24 5.645.60 10.3410.28 3,4003,2001,735 101 "      ##STR521##      --  1 powder 56.1356.28 6.816.59 12.1212.31 3,350 (broad)1,640 102      ##STR522##      ##STR523##      ##STR524##       1 162-165(dec.) 51.43 51.28 5.505.21 10.5010.21 3,370 3,2001,730 103 "      ##STR525##      --  1 powder 55.4055.28 6.626.32 12.4312.03 3,300 (broad)1,610 (broad)     104      ##STR526##      ##STR527##      ##STR528##       1 158-160(dec.) 52.7552.56 5.565.43 11.0410.97 3,4053,2201,740 105 "      ##STR529##      --  1 powder 56.2656.01 6.616.49 13.1313.21 3,320 (broad) 1,640     106     ##STR530##      ##STR531##      ##STR532##       1 160-163(dec.) 52.3352.03 5.605.30 10.6810.28 3,4003,2101,730 107 "      ##STR533##      --  1 powder 57.0257.39 6.816.21 12.7912.38 3,350 (broad)1,620 108      ##STR534##      ##STR535##      ##STR536##       1 152-155(dec.) 52.8352.53 5.735.72 10.5210.29 3,3903,2051,730 109 "      ##STR537##      --   1 powder 57.7357.51 7.007.23 12.4712.28 3,3701,630 110      ##STR538##      ##STR539##      ##STR540##       1 170-172(dec.) 51.4351.09 5.505.45 10.5010.28 3,3803,2201,740 111 "      ##STR541##      -- 5 1 powder 55.4055.30 6.626.28 12.4312.11 3,400-3,200(broad)1,600     112 "      ##STR542##      ##STR543##       1 155-158(dec.) 51.9452.29 5.64 5.63 10.3410.00 3,3803,2001,730 113 "      ##STR544##      --  1 powder 56.1356.40 6.816.61 12.1212.00 3,200-3,400(broad)1,600 114     "      ##STR545##      --  1 " 54.6354.40 6.426.30 12.7412.50 3,200-3,400(broad)1,600 115 "      ##STR546##      ##STR547##       1 165-170(dec.) 50.8150.68 5.585.43 10.6410.31 3,3803,2001,740 116 "      ##STR548##      --  1 powder 54.4354.70 6.766.71 12.7012.35 3,4001,590 117 "      ##STR549##      ##STR550##       1 164-166 51.3351.60 5.715.38 10.4810.25 3,3603,2001,735 118 "      ##STR551##      -- 2.0 1 powder 55.2155.00 6.956.30 12.3812.40 3,400-3,200(broad)1,570     119 "      ##STR552##      ##STR553##      1 168-172  52.7752.54 5.174.98 10.2610.21 3,3803,1801,740 120 "      ##STR554##      -- 2.5 1 powder 57.4257.35 6.025.84 11.9612.00 3,350-3,160(broad)1,600     121 "      ##STR555##      ##STR556##       1 130-135 53.2553.08 5.305.29 10.1110.29 3,4003,2001,730 122 "      ##STR557##      -- 1.5 1 powder 58.0857.84 6.226.13 11.6811.46 3,3603,1601,600 123 "      ##STR558##      ##STR559##       1 158-163(dec.) 51.9551.80 5.645.38 10.3410.30 3,3603,2001,740 124 "      ##STR560##      --  1 powder 56.1455.98 6.816.79 12.1312.35 3,380-3,200(broad)1,625 125      ##STR561##      ##STR562##      ##STR563##       1 160-163(dec.) 52.4452.39 5.765.58 10.1910.00 3,4003,2001,740 126 "      ##STR564##      -- 4.5 1 powder 56.8456.72 6.996.80 11.8411.76 3,380-3,250(broad)1,595     127      ##STR565##      ##STR566##      ##STR567##       1 160-165(dec.) 50.6250.39 5.405.28 11.1711.15 3,4003,2101,740 128 "      ##STR568##      --  1 powder 54.4354.27 6.556.28 13.8013.59 3,2801,590 129      ##STR569##      ##STR570##      -- 5 1 " 52.0751.89 6.376.39 12.6512.51 3,3603,2001,600 130      ##STR571##      ##STR572##      -- 20 5 210-213 54.8654.72 7.337.21 14.5414.27 3,3501,630 131      ##STR573##      ##STR574##      --  5 120-130 55.7355.82 7.527.50 14.1314.01 3,3501,630 132      ##STR575##      ##STR576##      -- 10 5 108-110 52.1552.21 6.886.71 14.4814.52 3,300 (broad)1,630 133      ##STR577##      ##STR578##      -- 30 5 powder 58.23 58.01 6.456.35 13.5813.46 3,300 (broad)1,635 134      ##STR579##      ##STR580##      --  5 powder 58.9658.91 6.666.79 13.2213.15 3,200 (broad)1,635 135      ##STR581##      ##STR582##      --  5 " 55.7355.81 7.527.40 14.1314.10 3,300 (broad)1,630 136 "      ##STR583##      --  5 170-173 57.5657.41 7.547.39 13.4313.50 3,3351,630 137      ##STR584##      ##STR585##      --  5 powder 56.7856.85 7.357.29 13.8013.71 3,200 (broad)1,630 138      ##STR586##      ##STR587##      --  5 " 58.9658.79 6.666.51 13.2213.19 3,300 (broad)1,630 139      ##STR588##      ##STR589##      --  5 142-145 49.0748.90 5.495.38 13.6313.42 3,1501,620 140      ##STR590##      ##STR591##      -- 5 powder 47.4747.29 5.435.31 12.5812.39 3,1501,630 141      ##STR592##      ##STR593##      -- 5 powder 49.0749.12 5.495.28 13.6313.59 3,1501,630 142      ##STR594##      ##STR595##      --  5 123-130 57.0156.88 6.986.71 13.8513.65 3,3001,635 143      ##STR596##      ##STR597##      -- 0.3 5 powder 56.1956.00 6.776.50 14.2514.00 3,3003,1501,630 144 "      ##STR598##      -- 0.2 5 " 53.5353.24 6.336.19 14.1913.99 3,300 (broad)1,630 145 "      ##STR599##      --  5 " 60.0957.79 6.166.02 12.9312.61 3,300 (broad)1,630 146 "      ##STR600##      -- 14 5 " 58.7358.66 7.016.90 13.1712.91 3,3801,635 147      ##STR601##      ##STR602##      --  5 147-150 52.5952.31 6.106.01 14.6114.333,3801,640 148      ##STR603##      ##STR604##      --  5 powder 57.2356.98 6.616.33 13.9113.81 3,300 (broad)1,630 149      ##STR605##      ##STR606##      --  5 " 58.6958.79 5.715.55 13.6913.39 3,300 (broad)3,1501,630 150 "      ##STR607##      --  5 " 56.1955.95 6.776.58 14.2513.97 3,190 (broad)1,620 151      ##STR608##      ##STR609##      -- 20 5 130-135 53.5352.28 6.336.19 14.1913.97 3,3501,640 152      ##STR610##      ##STR611##      -- 10 5 152-157 54.4254.28 6.556.32 13.8013.59 3,3501,635 153      ##STR612##      ##STR613##      -- 4 5 powder 55.3655.10 6.976.76 16.1416.07 3,3801,630 154 "      ##STR614##      --  5 " 52.8652.71 6.566.29 16.0816.07 155      ##STR615##      ##STR616##      --  5 powder 50.9050.81 5.905.70 14.13 13.89 3,180 (broad)1,630 156      ##STR617##      ##STR618##      --  5 " 59.4159.22 5.955.73 13.3313.28 3,170 (broad)1,620 157 "      ##STR619##      HCl  6 " 53.1752.89 6.696.52 12.9212.74 158 "      ##STR620##      HCl  6 " 57.6657.31 6.346.14 11.5911.16 159 "      ##STR621##      --  5 " 55.3355.26 6.546.62 14.6714.58 3,200 (broad)1,630 160      ##STR622##      ##STR623##      -- 0.25 1 " 55.4755.75 6.406.19 13.4813.26 3,350 (broad)1,6301,380 161     "      ##STR624##      -- 0.2 5 " 55.0555.28 7.127.00 13.3813.12 3,200 (broad)1.6351,380 162      ##STR625##      ##STR626##      -- 0.2 1 powder 54.2253.98 5.505.55 13.1813.24 3,320 (broad)1,6301,380     163 "      ##STR627##      --  1 " 57.2257.23 6.356.36 11.92 12.08 3,400 (broad)1,7401,620 164 "      ##STR628##      -- 0.15 1 " 53.8253.78 6.216.19 13.0812.86 3,360 (broad)1,6251,380 165     "      ##STR629##      --  1 " 56.8356.95 6.986.83 11.8411.98 3,400 (broad)1,7351,630 166      ##STR630##      ##STR631##      CH.sub.3 CO.sub.2      H  5 " 53.2853.13 6.626.82 13.8113.71 3,320 (broad)1,6301,140 167      ##STR632##      ##STR633##      --  5 " 51.1550.86 5.605.66 12.9712.87 3,320 (broad)1,6301,380 168      ##STR634##      ##STR635##      --  5 " 54.6453.36 6.186.00 13.8513.58 3,350 (broad)1,6401,390 169      ##STR636##      ##STR637##      --  5 powder 56.2755.98 6.616.78 13.1213.24 3,350(broad)1,6301,3801,140     170      ##STR638##      ##STR639##      --  5 " 54.2154.36 6.926.93 13.7413.76 3,300 (broad)1,6251,3801,160 171      ##STR640##      ##STR641##      --  1,2 " 53.0852.86 6.246.33 12.3812.41 3,300 (broad)1,6401,160 172 "      ##STR642##      --  1 " 56.0255.83 6.976.88 11.2711.28 3,400 (broad)1,7451,620 173      ##STR643##      ##STR644##      -- 0.2 3 " 57.2356.89 6.616.50 13.9113.70 3,390 (broad)1,625 174 "      ##STR645##      CH.sub.3      COOH  3 " 56.8356.72 6.986.81 11.8411.56 3,400 (broad)1,7351,640 175 "      ##STR646##      -- 0.1 2 " 58.7358.52 7.016.77 13.1713.00 3,380 (broad)1,620 176 "      ##STR647##      1/2 H.sub.2      SO.sub.3  2 " 55.9855.69 7.057.21 11.6611.38 3,400 (broad)1,7301,635     177      ##STR648##      ##STR649##      --  3 " 58.7358.81 7.027.03 13.1713.17 3,300 (broad)1,6151,380 178 "      ##STR650##      CH.sub.3      COOH  3 " 58.1357.98 7.327.56 11.3011.28 3,380 (broad)1,7301,630 179      ##STR651##      ##STR652##      -- 1 3 " 56.4256.38 6.386.52 14.3114.53 3,350 (broad)1,6201,160 180 "      ##STR653##      CH.sub.3      COOH  3 " 56.1356.08 6.806.83 12.1212.12 3,400 (broad)1,7401,630 181      ##STR654##      ##STR655##      -- 0.5 3 " 58.0057.83 6.826.77 13.5313.63 3,350 (braod)1,620 1,160 182     "      ##STR656##      CH.sub.3      COOH  3 " 57.5057.61 7.157.11 11.5611.81 3,350 (broad)1,7301,620 183      ##STR657##      ##STR658##      -- 0.35 3 " 55.5855.62 6.616.81 16.2116.03 3,350 (broad)1,6201,140 184      ##STR659##      ##STR660##      --  3 " 55.9656.12 7.157.28 14.1914.07 3,350 (broad)1,6201,150 185 "      ##STR661##      CH.sub.3      COOH  3 " 55.7455.90 7.457.51 12.04 12.18 3,400 (broad)1,7301,625 186      ##STR662##      ##STR663##      --  3 " 54.3854.08 6.215.91 12.6912.39 3,300 (broad)1,625 187      ##STR664##      ##STR665##      --  2 " 52.2552.36 6.035.98 12.7012.51 3,4001,7351,6401,160 188 "      ##STR666##      --  2 " 50.4650.61 5.585.63 13.3813.40 3,3801,6201,3801,155 189 "      ##STR667##      -- 2 3 " 52.0652.31 5.765.81  13.8013.51 3,3201,6201,3901,155 190 "      ##STR668##      -- 2 " 48.9649.13 5.425.38 12.9812.75 3,3501,6201,3801,150 191      ##STR669##      ##STR670##      -- 5 2 " 51.3851.45 5.815.86 13.0313.12 3,3501,6301,2551,150 192      ##STR671##      ##STR672##      --  2 " 49.5049.31 5.345.40 13.7513.68 3,3503,2001,622 193      ##STR673##      ##STR674##      --  2 " 58.2758.45 5.906.03 11.7211.53 3,3501,7401,6401,2601,160 194 "      ##STR675##      -- 2 2 " 57.6257.68 5.705.55 12.0011.73 3,300 (broad)1,6201,2501,150     195 "      ##STR676##      -- 1.5 3 " 56.9357.12 5.495.43 12.3012.14 3,3601,6251,2601,150 196 "      ##STR677##      -- 6.5 1 " 54.6354.28 6.426.31 12.7412.53 3,350 (broad)1,740 197 "      ##STR678##      --  2 " 53.8654.16 5.925.62 13.0012.70 3,100 (broad)1,620 198 "      ##STR679##      1/2 H.sub.2 SO.sub.3  2 " 54.5354.23 6.105.80 9.649.34 1,7201,630     (broad) 199      ##STR680##      ##STR681##      --  2 " 48.5548.31 4.934.64 11.8011.53 3,300 (broad)1,620 200      ##STR682##      ##STR683##      HCl 2 6 " 54.1053.81 7.327.13 10.18 9.93 3,180 (broad)1,7401,630 201 "      ##STR684##      --  2 " 57.2256.98 6.246.18 11.1211.31 3,3003,1501,7401,650 202 "      ##STR685##      HCl 20 6 " 54.0953.83 6.055.97 10.5110.36 3,2503,1001,7401,640 203 "      ##STR686##      HCl 30 6 " 55.5355.37 6.126.01 10.1210.01 3,3503,1501,7401,650 204      ##STR687##      ##STR688##      -- 4.5 2 " 48.9649.13 5.425.36 12.9813.01 3,3501,6201,380 205 "      ##STR689##      -- 2.5 2 " 54.6454.63 6.42 6.56 12.7413.01 3,3602,9401,6201,380 206      ##STR690##      ##STR691##      -- 12 2 " 59.8959.65 4.524.63 11.6411.81 3,3601,6201,2551,150 207 "      ##STR692##      -- 55 2 " 50.1549.91 6.416.35 14.0413.83 3,2801,620 208 "      ##STR693##      --  2 " 53.8553.61 5.935.76 13.0012.84 3,3201,610 209 "      ##STR694##      -- 2 2 " 57.4257.37 6.025.86 11.9611.74 3,300 (broad) 1,600 210      ##STR695##      ##STR696##      --  2 " 57.4157.33 6.035.94 11.9611.73 3,3001,610 211 "      ##STR697##      -- 2.5 2 " 53.9853.74 5.385.33 11.6611.74 3,3501,630 212      ##STR698##      ##STR699##      -- 6.5 2 " 52.0652.40 6.386.37 12.6512.73 3,350 (broad)1,620 213 "      ##STR700##      --  2 " 52.0751.95 6.376.27 12.6512.84 3,350 (broad)1.620 214 "      ##STR701##      -- 15 2 " 52.7552.68 6.366.34 13.3813.41 3,380 (broad)1,620 215 "      ##STR702##      --  2 " 50.9750.67 6.586.61 13.7213.39 3,200 (broad)1,610 (broad) 216 "      ##STR703##      1/2 H.sub.2 SO.sub.3  2 " 52.0151.77 6.696.50 10.1110.00 1,7251,620 217      ##STR704##      ##STR705##      --  5 " 46.1846.63 6.005.94 14.3714.23 3,4003,3001,630 218      ##STR706##      ##STR707##      --  5 " 51.3851.24 5.825.79 13.0312.87 3,3803,3001,630 219      ##STR708##      ##STR709##      --  1 " 52.1552.03 6.886.73 14.4814.68 3,3551,6301,3801,305 220      ##STR710##      ##STR711##      2H.sub.2 O 2 2 195-198 50.4250.48 6.546.16 12.2512.31 3,3201,620 221 "      ##STR712##      1/2 H.sub.2 O 15 2 229-233 52.94 52.73 6.306.15 12.8712.93 3,3501,620     222      ##STR713##      ##STR714##      -- 6.5 1 powder 48.7848.54 5.775.76 12.9313.15 3,3201,6201,390 223      ##STR715##      ##STR716##      --  1 " 50.2750.11 5.955.87 13.3313.34 3,3901,6301,2601,160 224      ##STR717##      ##STR718##      --  5 " 53.7653.66 5.955.83 14.2514.19 3,4003,2001,635 225      ##STR719##      ##STR720##      --  5 " 46.6246.53 6.386.21 14.3114.43 3,3503,1501,630 226      ##STR721##      ##STR722##      --  5 " 49.7149.84 7.027.26 13.1813.36 3,250 (broad)3,1501,630 227 "      ##STR723##      --  5 " 46.2446.31 6.406.53 13.4813.41 3,3203,1501,630 228      ##STR724##      ##STR725##      HCl  1 " 47.7447.53 6.756.51 14.6514.41 3,3403,1801,640 229      ##STR726##      ##STR727##        1  52.9552.79 6.005.87 13.4313.28 3,3503,1501,620 230 "      ##STR728##       1  53.16 5.64 13.48 231      ##STR729##      ##STR730##        5  40.7140.60 4.954.78 13.1913.03 3,3603,1501,620 232      ##STR731##      ##STR732##      --  3 " 55.5955.54 6.296.14 12.4712.35 3,3503,1501,625 233      ##STR733##      ##STR734##      --  3 " 57.4357.26 6.136.04 12.8812.71 3,3503,1301,615 234      ##STR735##      ##STR736##      --  5 " 46.8046.61 6.116.05 15.1615.23 3,3753,1501,630 235      ##STR737##      ##STR738##      --  3 " 50.8250.71 6.866.69 12.8912.57 3,3603,1201,620

The pharmaceutically acceptable salts of the above compounds are ofcourse also included within the scope of this invention.

For the preparation of the compounds of this invention, various methodscan be employed depending upon the particular starting materials and/orintermediates involved. Successful preparation of these compounds ispossible by way of several synthetic routes which are outlined below.

(a) Condensation of an L-argininamide with an arylsulfonyl halide Thisprocess may be illustrated as follows: ##STR739## In the above formulas,R and Ar are as defined herein above; X is halogen; R'" is a protectivegroup for the α-amino group, such as benzyloxycarbonyl ortert-butoxycarbonyl; R' and R" are selected from the group consisting ofhydrogen and protective groups for the guanidino group, such as nitro,tosyl, trityl, oxycarbonyl and the like; and at least one of R' and R"is a protective group for the guanidino group. The N²-arylsulfonyl-L-argininamide (I) is prepared by the condensation of anL-argininamide (VI) with a substantially equimolar amount of anarylsulfonyl halide (VII), preferably a chloride.

The condensation reaction is generally effected in a suitablereaction-inert solvent in the presence of an excess of a base, such ason organic base (triethylamine, pyridine) or a solution of an inorganicbase (sodium hydroxide, potassium carbonate), at a temperature of 0° Cto the boiling temperature of the solvent for a period of 10 minutes to15 hours.

The preferred solvents for the condensation include benzene-diethylether, diethyl ether-water and dioxane-water.

After the reaction is complete, the formed salt is extracted with water,and the solvent is removed by such standard means as evaporation underreduced pressure to give the N² -arylsulfonyl-L-argininamide (I), whichcan be purified by trituration or recrystallization from a suitablesolvent, such as diethyl ether-tetrahydrofuran, diethyl ether-methanoland water-methanol, or may be chromatographed on silica gel. TheL-argininamides (VI) starting materials required for the condensationreaction can be prepared by protecting the quanidino and α-amino groupsof L-arginine (II) via nitration, acetylation, formylation,phthaloylation, trifluoroacetylation, p-methoxybenzyloxycarbonylation,bezoylation, benzyloxycarbonylation, tert-butoxycarbonylation ortritylation and then condensing the formed N^(G) -substituted-N²-substituted-L-arginine (III) with a corresponding amino acid derivative(IV) by such a conventional process as the acid chloride method, azidemethod, mixed anhydride method, activated ester method or carbodiimidemethod, and thereafter selectively removing the protective groups fromthe formed N^(G) -substituted-N² -substituted-L-argininamide (V).

The amino acid derivatives (IV) which are the starting materials for thepreparation of the N^(G) -substituted-N² -substituted-L-argininamides(V) are represented by the following formulas: ##STR740## In the aboveformulas, R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₉, R₁₀, R₁₁, Z, n, m, r, q, i,and j are as defined herein above.

The amino acid derivatives of the above formula (VIII) or (IX) can beprepared by the condensation of a haloacetate, 3-halopropionate or4-halobutyrate with an appropriate amine having the formula R₁ NH₂ or R₃NH₂. (See, J. Org. Chem., 25 728-732 (1960)).

The condensation reaction is generally carried out without a solvent orin a solvent, such as benzene or ether, in the presence of an organicbase, such as triethylamine or pyridine, at a temperature of 0° to 80° Cfor a period of 10 minutes to 20 hours. After the reaction is complete,the formed amino acid derivative is separated by such conventional meansas extraction with a suitable solvent or evaporation of the reactionsolvent and thereafter purified by distillation under reduced pressure.

Among the amino acid derivatives, amino acid tert-butyl esterderivatives are preferred, because they are easily converted to otherester derivatives by acidolysis in the presence of a correspondingalcohol employing an inorganic acid (HCl, H₂ SO₄, etc.) or an organicacid (toluenesulfonic acid, trifluoroacetic acid, etc.). In accordancewith the process employed for preparing 2-piperidinecarboxylic acidderivatives (X), the following scheme is illustrative: ##STR741## In thefirst reaction of the aforementioned scheme, an appropriatelysubstituted piperidine (XIV) Is contacted with an aqueous sodiumhypochlorite solution at a temperature of -5° to 0° C. The resultantproduct (XV) is isolated by extraction with a solvent, e.g., diethylether, and then treated with potassium hydroxide in a lower alkanolsolvent to give the 1,2-dehydropiperidine (XVI). The action ofcyanogenating agents, e.g., hydrogen cyanide or sodium cyanide convertsthe 1,2-dehydropiperidines (XVI) to the corresponding 2-cyano analogs(XVII). Hydrolysis of the 2-cyanopiperidines (XVII) to yield the2-piperidinecarboxylic acids (XVIII) Is effected by treatment of the2-cyanopiperidines (XVII) with an inorganic acid, such as hydrochloricacid or sulfuric acid.

The arylsulfonyl halides (VII) which are the starting materials for thepreparation of the N² -arylsulfonyl-L-argininamides (I) can be preparedby halogenating the requisite arylsulfonic acids or their salts, e.g.,sodium salts, by conventional methods well known to those skilled in theart. In practice, halogenation is carried out without a solvent or in asuitable solvent e.g., halogenated hydrocarbons or DMF in the presenceof a halogenating agent, e.g., phosphorous oxychloride, thionylchloride, phosphorous trichloride, phosphorous tribromide or phosphorouspentachloride, at a temperature of -10° to 200° C for a period of 5minutes to 5 hours. After the reaction is complete, the reaction productis poured into ice water and then extracted with a solvent such asether, benzene, ethyl acetate, chloroform or the like.

The arylsulfonyl halide can be purified by recrystallization from asuitable solvent such as hexane, benzene or the like.

(b) Removal of the N^(G) -substituent from an N^(G) -substituted-N²-arylsulfonyl-L-argininamide This process may be illustrated as follows:##STR742## In the above formulas, R, Ar, X, R', R" and R'" are asdefined herein above.

The N² -arylsulfonyl-L-argininamide (I) is prepared by removing theN^(G) -substituent from an N^(G) -substituted-N²-arylsulfonyl-L-argininamide (XX) by means of acidolysis orhydrogenolysis.

The acidolysis is generally effected by contacting the N^(G)-substituted-N² -arylsulfonyl-L-argininamide (XX) and an excess of anacid such as hydrogen fluoride, hydrogen chloride, hydrogen bromide ortrifluoroacetic acid, without a solvent or in a solvent, such as anether (tetrahydrofuran, dioxane), an alcohol (methanol, ethanol) oracetic acid at a temperature of -10° to 100° C, and preferably at roomtemperature for a period of 30 minutes to 24 hours.

The products are isolated by evaporation of the solvent and the excessacid, or by trituration with a suitable solvent followed by filtrationand drying.

Because of the use of the excess acid, the products are generally theacid addition salts of the N² -arylsulfonyl-L-argininamides (I), whichcan be easily converted to a free amide by neutralization.

The removal of the nitro group and the oxycarbonyl group, e.g.,benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, is readily accomplished bythe hydrogenolysis. At the same time, the benzyl ester moiety which canbe included in the R group is converted to the carboxyl group by thehydrogenolysis.

The hydrogenolysis is effected in a reaction-inert solvent, e.g.,methanol, ethanol, tetrahydrofuran or dioxane, in the presence of ahydrogen-activating catalyst, e.g., Raney nickel, palladium, orplatinum, in a hydrogen atmosphere at a temperature of 0° C to theboiling temperature of the solvent for a period of 2 hours to 120 hours.

The hydrogen pressure is not critical, and atmospheric pressure issufficient.

The N² -arylsulfonyl-L-argininamides (I) are isolated by filtration ofthe catalyst followed by evaporation of the solvent.

The N² -arylsulfonyl-L-argininamides can be purified in the same manneras described above.

The N^(G) -substituted-N² -arylsulfonyl-L-argininamides (XX) startingmaterials can be prepared by condensing an N^(G) -substituted-N²-substituted-L-arginine (III) (generally the N² -substituent is nitro oracyl, and the N² -substituent is a protective group for the amino group,such as benzyloxycarbonyl, tert-butoxycarbonyl, or the like) and acorresponding amino acid derivative (IV), selectively removing only theN² -substituent of an N^(G) -substituted-N^(a) -substitutedL-argininamide (V) by means of catalytic hydrogenolysis or acidolysis,and then condensing the thus obtained N^(G) -substituted-L-argininamide(XIX) with an arylsulfonyl halide (VII), preferably a chloride in thepresence of a base in a solvent. These reaction conditions are asdescribed above in the condensation of an L-argininamide with anarylsulfonyl halide, and the removal of the N^(G) -substituent from anN^(G) -substituted-N² -arylsulfonyl-L-argininamide.

(c) Condensation of an N² -arylsulfonyl-L-arginyl halide with an aminoacid derivative This process may be illustrated as follows: ##STR743##In the above formulas, R, Ar and X are as defined herein above.

The N² -arylsulfonyl-L-argininamide (I) is prepared by the condensationof an N² -arylsulfonyl-L-arginyl halide (XXII), preferably a chloridewith at least an equimolar amount of an amino acid derivative (IV). Thecondensation reaction can be carried out without an added solvent in thepresence of a base. However, satisfactory results will be obtained withthe use of a solvent such as basic solvents (dimethylformamide,dimethylacetamide, etc.) or halogenated solvents (chloroform,dichloromethane, etc.).

The amount of the solvent to be used is not critical and may vary fromabout 5 to 100 times the weight of the N² -arylsulfonyl-L-arginyl halide(XXII).

Preferred condensation reaction temperatures are in the range of from-10° C to room temperature. The reaction time is not critical, butvaries with the amino acid derivative (IV) employed. In general, aperiod of from 5 minutes to 10 hours is operable. The obtained N²-arylsulfonyl-L-argininamide can be isolated and purified in the samemanner as described above.

The N² -arylsulfonyl-L-arginyl halide (XXII) starting materials requiredfor the condensation reaction can be prepared by reacting an N²-arylsulfonyl-L-arginine (XXI) with at least an equimolar amount of ahalogenating agent such as thionyl chloride, phosphorous oxychloride,phosphorus trichloride, phosphorous pentachloride or phosphorustribromide. The halogenation can be carried out with or without an addedsolvent. The preferred solvents are chlorinated hydrocarbons such aschloroform and dichloromethane, and ethers such as tetrahydrofuran anddioxane.

The amount of the solvent to be used is not critical and may vary fromabout 5 to 100 times the weight of the N² -arylsulfonyl-L-arginine(XXI).

Preferred reaction temperature are in the range of -10° C to roomtemperature. The reaction time is not critical, but varies with thehalogenating agent and reaction temperature. In general, a period of 15minutes to 5 hours is operable.

The N² -arylsulfonyl-L-arginines (XXI) which are the starting materialsfor the preparation of the N² -arylsulfonyl-L-arginyl halides (XXII) canbe prepared by the condensation of L-arginine (II) with a substantiallyequimolar amount of arylsulfonyl halides (VII), by a method similar tothat described in the condensation of an L-argininamide with anarylsulfonyl halide.

(d) Guanidylation of an N² -arylsulfonyl-L-ornithinamide or an acidaddition salt thereof This process may be illustrated as follows:##STR744## In the above formulas, R and Ar are as defined herein above.

The N² -arylsulfonyl-L-argininamide (I) is prepared by guanidylating anN² -arylsulfonyl-L-ornithinamide (XXIII) with an ordinary guanidylatingagent such as an O-alkylisourea, S-alkylisothiourea,1-guanyl-3,5-dimethylpyrazole or carbodiimide. The preferredguanidylating agents are the O-alkylisourea and the S-alkylisothiourea.

The guanidylation of the N² -arylsulfonyl-L-ornithinamide (XXIII) withthe O-alkylisourea or S-alkylisothiourea is generally effected in asolvent in the presence of a base at a temperature of from 0° C to theboiling temperature of the solvent for a period of from 30 minutes to 50hours.

Examples of the preferred bases are triethylamine, pyridine, sodiumhydroxide and sodium methoxide. The base is used in an amount of 0.01 to0.1 equivalent to the N² -arylsulfonyl-L-ornithinamide.

Examples of the preferred solvents are water, water-ethanol andwater-dioxane.

After the reaction is complete, the N² -arylsulfonyl-L-argininamide (I)is isolated by evaporation of the solvent followed by removal of theexcess base and the formed salt by a water wash.

It is well recognized in the art that an ester derivative of the N²-arylsulfonyl-L-argininamide (I) wherein R₂, R₅, R₈, R₉, R₁₀ or R₁₁ isalkyl, aralkyl, aryl or 5-indanyl, can be prepared from a carboxylicacid derivative of the N² -arylsulfonyl-L-argininamide wherein R₂, R₅,R₈, R₉, R₁₀ or R₁₁ is hydrogen, by the conventional esterificationmethods well known to those skilled in the art. It is also wellrecognized in the art that the carboxylic acid derivative can beprepared from the ester derivative by the conventional hydrolysis oracidolysis methods. The conditions under which esterification,hydrolysis or acidolysis would be carried out will be each apparent tothose skilled in the art.

The N² -arylsulfonyl-L-argininamide (I) of this invention forms acidaddition salts with any of a variety of inorganic and organic acids.Some of the N² -arylsulfonyl-L-argininamides containing a free carboxylgroup, wherein R₂, R₅, R₈, R₉, R₁₀ or R₁₁ is hydrogen, forms salts withany of a variety of inorganic and organic bases.

The product of the reactions described above can be isolated in the freeform or in the form of salts. In addition, the product can be obtainedas pharmaceutically acceptable acid addition salts by reacting one ofthe free bases with an acid, such as hydrochloric, hydrobromic,hydroiodic, nitric, sulfuric, phosphoric, acetic, citric, maleic,succinic, lactic, tartaric, gluconic, benzoic, methanesulfonic,ethanesulfonic, benzenesulfonic, p-toluenesulfonic acid or the like. Ina similar manner, the product can be obtained as pharmaceuticallyacceptable salts by reacting one of the free carboxylic acids with abase, such as sodium hydroxide, potassium hydroxide, ammonium hydroxide,triethylamine, procaine, dibenzylamine, 1-ephenamine,N,N'-dibenzylethylenediamine, N-ethylpiperidine or the like.

Likewise, treatment of the salts with a base or acid results in aregeneration of the free amide.

As stated above, the N² -arylsulfonyl-L-argininamides, and the saltsthereof of this invention are characterized by their highly specificinhibitory activity in mammals against thrombim as well as by theirsubstantial lack of toxicity, and therefore these compounds are usefulin the determination of thrombin in blood as diagnostic reagents, and/orfor the medical control or prevention of thrombosis.

The compounds of this invention are also useful as an inhibitor ofplatelet aggregation.

The antithrombotic activity of the N² -arylsulfonyl-L-argininamide ofthis invention was compared with that of a known antithrombotic agent,N² -(p-tolylsulfonyl)-L-arginine methyl ester, by determining thefibrinogen coagulation time. The measurement of the fibrinogencoagulation time was conducted as follows:

An 0.8 ml aliquot of a fibrinogen solution, which had been prepared bydissolving 150 mg of bovine fibrinogen (Cohn fraction I) supplied byArmour Inc. in 40 ml of a borate saline buffer (pH 7.4), was mixed with0.1 ml of a borate saline buffer, pH 7.4, (control) or a sample solutionin the same buffer, and 0.1 ml of a thrombin solution (5 units/ml)supplied by Mochida Pharmaceutical Co., Ltd. was added to the solutionsin an ice bath.

Immediately after mixing, the reaction mixture was transferred from theice bath to a bath maintained at 25° C. Coagulation times were taken asthe period between the time of transference to the 25° C bath and thetime of the first appearance of fibrin threads. In the cases where nodrug samples were added, the coagulation time was 50-55 seconds. Theexperimental results are summarized in Table 2. The term "concentrationrequired to prolong the coagulation time by a factor of two" is theconcentration of an active ingredient required to prolong the normalcoagulation time 50-55 seconds to 100-110 seconds.

The concentration required to prolong the coagulation time by a factorof two for the known antithrombotic agent, N²-(p-tolylsulfonyl)-L-arginine methyl ester, was 1,100μm. The inhibitorsare shown in Table 1 by indicating R and Ar in the formula (I) and theaddition moiety.

When a solution containing an N² -naphthylsulfonyl-L-argininamide ofthis invention was administered intravenously into animal bodies, thehigh antithrombotic activity in the circulating blood was maintained forfrom 1 to 3 hours. The halflife for decay of the anti-thromboticcompounds of this invention in circulating blood was shown to beapproximately 60 minutes; the physiological conditions of the hostanimals (rat, rabbit, dog and chimpanzee) were well maintained. Theexperimental decrease of fibrinogen in animals caused by infusion ofthrombin was satisfactorily controlled by simultaneous infusion of thecompounds of this invention.

The acute toxicity values (LD₅₀) determined by intraperitonealadministration of substances of formula (I) in mice (male, 20 g) rangefrom about 1,000 to 10,000 milligrams per kilogram of body weight.

Representative LD₅₀ values for the compounds of this invention are shownin the following Table.

    ______________________________________    Compound                LD.sub.50 (mg/kg)    ______________________________________    N.sup.2 -(7-methyl-2-naphthylsulfonyl)-L-    arginyl-N-butylglycine  > 1,500    N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-    arginyl-N-(2-methoxyethyl)glycine                            1,900-2,400    N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-    arginyl-N-(2-ethoxyethyl)-β-alanine                            660-1,000    N.sup.2 -(4,6-dimethoxy-2-naphthylsulfonyl)-L-    arginyl-N-(2-methoxyethyl)glycine                            660-1,000    N.sup.2 -(7-methoxy-2-naphthylsulfonyl)-L-    arginyl-N-(2-methoxyethyl)glycine                            2,000    N.sup.2 -(5,6,7,8-tetrahydro-1-naphthylsulfonyl)-    L-arginyl-N-(2-methoxyethyl)glycine                            > 1,500    N.sup.2 -(6,7-dimethyl-1-naphthylsulfonyl)-L-    arginyl-N-(2-methoxyethyl)glycine                            >1,500    N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-    arginyl-N-(2-ethylthioethyl)glycine                            >1,000    N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-    arginyl-N-benzylglycine >1,000    N.sup.2 -(4,6-dimethoxy-2-naphthylsulfonyl)-L-    arginyl-N-benzylglycine >1,000    N.sup.2 -(5-methoxy-1-naphthylsulfonyl)-L-    arginyl-N-benzylglycine >1,000    N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-    arginyl-N-phenethylglycine                            >1,500    N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-                            1,500    arginyl-N-cyclohexylglycine                            >1,500    N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-    arginyl-N-cyclohexylmethylglycine                            >1,500    N.sup.2 -(7-methyl-2-naphthylsulfonyl)-L-    arginyl-N-tetrahydrofurfurylglycine                            600    N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-    arginyl-N-tetrahydrofurfurylglycine                            620    N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-    arginyl-N-butylalanine  >1,500    N.sup.2 -(4,6-dimethoxy-2-naphthylsulfonyl)-L-    arginyl-N-cyclohexylmethylalanine                            >1,500    1- N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-    arginyl!-2-piperidinecarboxylic acid                            1,500    Ethyl 1-N.sup.2 -(7-methoxy-2-naphthylsulfonyl)-    L-arginyl!-4-methyl-2-piperidinecarboxylate                            670-1,000    1- N.sup.2 -(4,6-dimethoxy-2-naphthylsulfonyl)-    L-arginyl!-4-methyl-2-piperidinecarboxylic                            670-1,000    acid    1- N.sup.2 -(1-naphthylsulfonyl)-L-arginyl!-4-    methyl-2-piperidinecarboxylic acid                            700-1,000    1- N.sup.2 -(5-dimethylamino-1-naphthylsulfonyl)-    L-arginyl!-2-piperidinecarboxylic acid                            700-1,000    4- N.sup.2 -(7-methoxy-2-naphthylsulfonyl)-L-    arginyl!-3-morpholinecarboxylic acid                            >1,000    2- N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-    arginyl!-1,2,3,4-tetrahydroisoquinoline-3-                            >1,000    carboxylic acid    2- N.sup.2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-    arginyl!-1-isoindolinecarboxylic acid                            >1,000    ______________________________________

On the other hand, LD₅₀ values for N² -dansyl-N-butyl-L-argininamide andN² -dansyl-N-methyl-N-butyl-L-argininamide are 75 and 70 milligrams perkilogram, respectively.

The therapeutic agents in this invention may be administered to mammals,including humans, alone or in combination with pharmaceuticallyacceptable carriers, the proportion of which is determined by thesolubility and chemical nature of the compound, chosen route ofadministration and standard pharmaceutical practice. For example, thecompounds may be injected parenterally, that is, intramuscularly,intravenously or subcutaneously. For parenteral administration, thecompounds may be used in the form of sterile solutions containing othersolutes, for example, sufficient saline or glucose to make the solutionisotonic. The compounds may be administered orally in the form oftablets, capsules, or granules containing suitable excipients such asstarch, lactose, white sugar and the like. The compounds may beadministered sublingually in the form of troches or lozenges in whicheach active ingredient is mixed with sugar or corn syrups, flavoringagents and dyes, and then dehydrated sufficiently to make the mixturesuitable for pressing into solid form. The compounds may be administeredorally in the form of solutions which may contain coloring and flavoringagents. Physicians will determine the dosage of the present therapeuticagents which will be most suitable for humans, and dosages vary with themode of administration and the particular compound chosen. In addition,the dosage will vary with the particular patient under treatment. Whenthe composition is administered orally, a larger quantity of the activeagent will be required to produce the same effect as caused with asmaller quantity given parenterally. The therapeutic dosage is generally10-50 mg/kg of active ingredient parenterally, 10-500 mg/kg orally perday. Having generally described the invention, a more completeunderstanding can be obtained by reference to certain specific examples,which are included for purposes of illustration only and are notintended to be limiting unless otherwise specified.

It is to be understood that the present invention includespharmaceutical compositions containing a compound of the invention as anactive ingredient. Such compositions may be in the forms describedabove. In particular, the invention includes such compositions in unitdose form.

EXAMPLE 1 (A) N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginine

To a well stirred solution of 83.6 g of L-arginine in 800 ml of 10%potassium carbonate solution was added 114.7 g of6,7-dimethoxynaphthalenesulfonyl chloride in 800 ml of benzene. Thereaction mixture was stirred at 60° C for 5 hours, during which time theproduct precipitated. After one hour at room temperature, theprecipitate was filtered and washed successively with benzene and waterto give 129 g (76 percent) of N²-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginine, M.P. 252°-5° C.

(B) N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl chloride

A suspension of 2.00 g of N²-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginine in 20 ml of thionylchloride was stirred for 2 hours at room temperature. Addition of colddry diethyl ether resulted in a precipitate which was collected byfiltration and washed several times with dry diethyl ether to give N²-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl chloride.

(C) N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylglycinetert-butyl ester

To a stirred solution of 2.64 g of N-butylglycine tert-butyl ester in 20ml of chloroform was carefully added N²-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl chloride obtained above.The reaction mixture was allowed to stand at room temperature for onehour. At the end of this period, the reaction mixture was washed twicewith 20 ml of saturated sodium chloride solution and evaporated todryness.

The residue was triturated with a small amount of water to give acrystalline material. This was collected by filtration andrecrystallized from ethanol-ethyl ether to give 2.28 g (82 percent) ofN² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylglycinetert-butyl ester, M.P. 164°-166° C, I.R. (KBr): 3,390, 3,165, 1,735,1,370 cm⁻¹.

Analysis - Calcd. for C₂₈ H₄₃ O₇ N₅ S.1/2H₂ SO₃ (percent): C, 52.98; H,7.00; N, 11.04 Found (percent): C, 52.69; H, 6.98; N, 10.86

(D) N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylglycine

To a solution of 2.00 g of N²-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylglycine tert-butylester in 20 ml of chloroform was added 50 ml of 15% HCl-ethyl acetate.The reaction mixture was stirred for 5 hours at room temperature. At theend of this period, the reaction mixture was evaporated to dryness. Theresidue was washed several times with dry diethyl ether andchromatographed on 80 ml of Daiaion ® SK 102 ion exchange resin (200-300mesh, H⁺ form, manufactured by Mitsubishi Chemical Industries Limited)packed in water, washed with water and eluted with 3% ammonium hydroxidesolution.

The fraction eluted from 3% ammonium hydroxide solution was evaporatedto dryness to give 1.43 g (79 percent) of N²-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylglycine as anamorphous solid, I.R. (KBr): 3,360, 3,140, 1,622 cm⁻¹.

Analysis -Calcd. for C₂₄ H₃₅ N₅ O₇ S (percent): C, 53.62; H, 6.56; N,13.03 Found (percent): C, 53.48; H, 6.43; N, 12.98

The following compounds are prepared in a similar manner:

N² -(7-methyl-2-naphthylsulfonyl)-L-arginyl-N-butyl-β-alanine

N²-(7-methyl-2-naphthylsulfonyl)-N-(2-methoxyethyl)-N-(3-carboxypropyl)-L-argininamide

N²-(5-methoxy-1-naphthylsulfonyl)-L-arginyl-N-(2-methylthioethyl)glycine

N²-(5-methoxy-1-naphthylsulfonyl)-L-arginyl-N-(2-methylthioethyl)glycinetert-butyl ester

N²-(5-methoxy-1-naphthylsulfonyl)-L-arginyl-N-(2-methylthioethyl)-β-alanine

N²-(6,7-diethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methylthioethyl)glycine

N²-(6-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methylthioethyl)glycine

N²-(6,7-dimethoxy-2-naphthylsulfonyl)-N-(2-methylthioethyl)-N-(3-carboxypropyl)-L-argininamide

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-N-(3-methylthiopropyl)glycine

N²-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-ethylthioethyl)-β-alanine

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-benzylglycine benzylester

N²-(6,7-dimethoxy-2-naphthylsulfonyl)-N-benzyl-N-(3-tert-butoxycarbonylpropyl)-L-argininamide

N² -(6,7-diethoxy-2-naphthylsulfonyl)-L-arginyl-N-cyclohexylglycine

4-N- N²-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl!-N-cyclohexylaminobutyricacid

N² -(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-phenethyl-β-alanine

N² -(6-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(3-phenylpropyl)glycine

N² -(5-methoxy-1-naphthylsulfonyl)-L-arginyl-N-benzyl-β-alanine

N² -(5-nitro-1-naphthylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine

N² -(7-hydroxy-2-naphthylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine

N² -(5-cyano-1-naphthylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine

N²-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-tetrahydrofurfuryl-β-alanine

N²-(7-methyl-2-naphthylsulfonyl)-L-arginyl-N-tetrahydrofurfuryl-β-alanine

N²-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-tetrahydrofurfurylalanine

N²-(7-methoxy-2-naphthylsulfonyl)-N-(3-carboxypropyl)-N-tetrahydrofurfuryl-L-argininamide

N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-butylalanine

N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-pentylalanine

N² -(5-methoxy-1-naphthylsulfonyl)-L-arginyl-N-butylalanine

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-isobutylalanine

N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-benzylalanine

N²-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(3-phenylpropyl)alanine

N² -(5-methoxy-1-naphthylsulfonyl)-L-arginyl-N-benzylalanine

N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-cyclohexylalanine

N²-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-cyclohexylmethylalanine

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylbutyrine

N²-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(3-furylmethyl)glycine

N²-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(tetrahydro-3-furylmethyl)glycine

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-thenyl)glycine

N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(3-thenyl)glycine

N²-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(tetrahydro-2-thenyl)glycine

N²-(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-)Tetrahydro-3-thenyl)glycine

N₂-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-acetylethyl)glycine

N₂ -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(4-methoxyfuryl)glycine

N₂ -(7-methyl-2-naphthylsulfonyl)-L-arginyl-N-(5-methylfurfuryl)glycine

N₂-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(1,4-diacylohexylmethyl)glycine

1-(N₂ -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl)-4-methoxypiperidine-2-carbonxylic acid

1-(N₂-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl)-5-methyl-hexamethyleneimine-2-carbonxylicacid

1-(N₂-(3,7-dimethyl-2-dibenzofluranyl)-L-arginyl)-4,4-dimethyl-2-piperidinecarboxylic acid

N₂-(3-methoxy-5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl-N-(tetrahydro-2-pyranylmethyl)glycine

EXAMPLE 2 (A) N² -(6-methoxy-2-naphthylsulfonyl)-L-arginyl chloride

A suspension of 2.5 g of N² -(6-methoxy-2-naphthylsulfonyl)-L-argininein 20 ml of thionyl chloride was stirred for 2 hours at roomtemperature. Addition of cold dry ethyl ether resulted in a precipitatewhich was collected by filtration and washed several times with dryethyl ether to give N² -(6-methoxy-2-naphthylsulfonyl)-L-arginylchloride.

(B) Ethyl 1- N²-(6-methoxy-2-naphthylsulfonyl)-L-arginyl!-2-piperidinecarboxylate

To a stirred solution of 2.2 g of ethyl 2-piperidinecarboxylate and 4.1ml of triethylamine in 50 ml of chloroform, which was cooled in anice-salt bath, was added in portions N²-(6-methoxy-2-naphthylsulfonyl)-L-arginyl chloride obtained above. Thereaction mixture was stirred overnight at room temperature. At the endof this period, 500 ml of chloroform was added and the chloroformsolution was washed twice with 50 ml of saturated sodium chloridesolution, dried over anhydrous sodium sulfate and evaporated in vacuo.The oily residue was washed with ethyl ether to give 2.9 g of powderyethyl 1- N²-(6-methoxy-2-naphthylsulfonyl)-L-arginyl!-2-piperidinecarboxylate. Foranalysis of the product, a portion of the product was converted to theflavianate, M.P. 192°-3° C. I.R. (KBr): 3,210, 1,747, 1,638 cm⁻¹

Analysis - Calcd. for C₂₅ H₃₅ O₆ N₅ S.C₁₀ H₆ O₈ N₂ S (percent): C,49.58; H, 4.87; N, 11.56 Found (percent): C, 49.24; H, 4.70; N, 11.85

(C) 1- N²-(6-methoxy-2-naphthylsulfonyl)-L-arginyl!-2-piperidinecarboxylic acid

A solution of 2.8 g of ethyl 1- N²-(6-methoxy-2-naphthylsulfonyl)-L-arginyl!-2-piperidinecarboxylate in 15ml of methanol and 10 ml of 2N-NaOH solution was warmed to 60° C andheld at that temperature for 10 hours. At the end of this period, thereaction mixture was concentrated and chromatographed on 200 ml ofDaiaion .sup.® SK 102 ion exchange resin (200 - 300 mesh, H⁺ form,manufactured by Mitsubishi Chemical Industries Limited) packed in water,washed with ethanol-water (1:4) and eluted with ethanol-water-NH₄ OH(10:9:1). The main fraction was evaporated to dryness and washed withethyl ether to give 2.0 g of 1- N²-(6-methoxy-2-naphthylsulfonyl)-L-arginyl!-2-piperidinecarboxylic acidas an amorphous solid. I.R. (KBr): 3,200 (broad), 1,620, 1,150 cm⁻¹

Analysis - Calcd. for C₂₃ H₃₁ O₆ N₅ S (percent): C, 54.64; H, 6.18; N,13.85 Found (percent): C, 56.88; H, 6.31; N, 13.83

The following compounds are prepared in a similar manner:

N² -(6-chloro-2-naphthylsulfonyl)-L-arginyl-N-butylglycine

N² -(7-methyl-2-naphthylsulfonyl)-L-arginyl-N-(2-ethoxyethyl)-glycine

N²-(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methylthioethyl)glycine

N²-(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methylthioethyl)glycine

N² -(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-phenethyl-β-alanine

N²-(6,7-dimethoxy-2-naphthylsulfonyl)-N-benzyl-N-(3-carboxypropyl)-L-argininamide

N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-cyclohexylnorleucine

N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-butylisoleucine

N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-pentylbutyrine

N² -(6,7-diethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylalanine

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-cycloheptylalanine

N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)alanine

N²-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-ethoxyethyl)alanine

N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-cyclohexyl-β-alanine

N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)norvaline

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-benzylleucine

1- N²-(5-methoxy-1-naphthylsulfonyl)-L-arginyl!-4-ethyl-2-piperidinecarboxylicacid

1- N²-(6-methoxy-2-naphthylsulfonyl)-L-arginyl!-4-ethyl-2-piperidinecarboxylicacid

1- N²-(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl!-4-ethyl-2-piperidinecarboxylicacid

1- N²-(5-ethoxy-1-naphthylsulfonyl)-L-arginyl!-4-ethyl-2-piperidinecarboxylicacid

1- N²-(7-ethoxy-2-naphthylsulfonyl)-L-arginyl!-4-ethyl-2-piperidinecarboxylicacid

1- N²-(6,7-diethoxy-2-naphthylsulfonyl)-L-arginyl!-4-ethyl-2-piperidinecarboxylicacid

1- N²-(7-methoxy-2-naphthylsulfonyl)-L-arginyl!-4-tert-butyl-2-piperidinecarboxylicacid

Phenyl 1- N²-(7-methoxy-2-naphthylsulfonyl)-L-arginyl!-4-ethyl-2-piperidinecarboxylate

Benzyl 1- N²-(7-methoxy-2-naphthylsulfonyl)-L-arginyl!-4-ethyl-2-piperidinecarboxylate

Benzyl 1- N²-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl!-4-methyl-2-piperidinecarboxylate

1- N²-(5-nitro-1-naphthylsulfonyl)-L-arginyl!-4-methyl-2-piperidinecarboxylicacid

1- N²-(7-hydroxy-2-naphthylsulfonyl)-L-arginyl!-4-ethyl-2-piperidinecarboxylicacid

1- N²-(5-cyano-1-naphthylsulfonyl)-L-arginyl!-4-methyl-2-piperidinecarboxylicacid

1- N²-(7-methyl-2-naphthylsulfonyl)-L-arginyl!-4-ethyl-2-piperidinecarboxylicacid

1- N²-(5-dimethylamino-1-naphthylsulfonyl)-L-arginyl!-4-ethyl-2-piperidinecarboxylicacid

1- N² -(2-naphthylsulfonyl)-L-arginyl!-4-ethyl-2-piperidinecarboxylicacid

1- N²-(5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl!-4-ethyl-2-piperidinecarboxylicacid

1- N²-(5-dimethylamino-1-naphthylsulfonyl)-L-arginyl!-4-methyl-2-piperidinecarboxylicacid

1- N²-(7-methyl-2-naphthylsulfonyl)-L-arginyl!-6-methyl-2-piperidinecarboxylicacid

1- N²-(7-methyl-2-naphthylsulfonyl)-L-arginyl!-4-tert-butyl-2-piperidinecarboxylicacid

1- N² -(5-nitro-1-naphthylsulfonyl)-L-arginyl!indoline-2-carboxylic acid

2- N² -(5-cyano-1-naphthylsulfonyl)-L-arginyl!isoindoline-1-carboxylicacid

4- N²-(7-methoxy-2-naphthylsulfonyl)-L-arginyl!thio-morpholine-3-carboxylicacid

4- N²-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl!morpholine-3-carboxylicacid

4- N²-(5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl!-3-carboxythiomorpholine1-oxide

4- N² -(7-methyl-2-naphthylsulfonyl)-L-arginyl!morpholine-3-carboxylicacid

4- N² -(7-chloro-2-naphthylsulfonyl)-L-arginyl!morpholine-3-carboxylicacid

4- N² -(7-hydroxy-2-naphthylsulfonyl)-L-arginyl!morpholine-3-carboxylicacid

4- N²-(5-nitro-1-naphthylsulfonyl)-L-arginyl!thiomorpholine-3-carboxylic acid

4- N²-(5-cyano-1-naphthylsulfonyl)-L-arginyl!thiomorpholine-3-carboxylic acid

4- N² -(5-methoxy-1-naphthylsulfonyl)-L-arginyl!morpholine-3-carboxylicacid

Ethyl 4- N²-(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl!morpholine-3-carboxylate

4- N² -(5-ethoxy-1-naphthylsulfonyl)-L-arginyl!morpholine-3-carboxylicacid

4- N²-(5-dimethylamino-1-naphthylsulfonyl)-L-arginyl!thiomorpholine-3-carboxylicacid

3- N² -(1-naphthylsulfonyl)-L-arginyl!thiazolidine-4-carboxylic acid

2- N²-(7-methoxy-2-naphthylsulfonyl)-L-arginyl!-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid

2- N² -(7-methoxy-2-naphthylsulfonyl)-L-arginyl!isoindoline-1-carboxylicacid

2- N²-(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl!-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid

2- N² -(5-methoxy-1-naphthylsulfonyl)-L-arginyl!isoindoline-1-carboxylicacid

2- N²-(5-ethoxy-1-naphthylsulfonyl)-L-arginyl!-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid

EXAMPLE 3 (A) N^(G) -nitro-N²-(tert-butoxycarbonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ether

To a stirred solution of 28.3 g of N^(G) -nitro-N²-(tert-butoxycarbonyl)-L-arginine in 450 ml of dry tetrahydrofuran wereadded in turn 12.4 ml of triethylamine and 12.4 ml of isobutylchloroformate while keeping the temperature at -5° C. After 15 minutes,to this was added 14.2 g of N-(2-methoxyethyl)glycine ethyl ester, andthe mixture was stirred for 15 minutes at -5° C. At the end of thisperiod, the reaction mixture was warmed to room temperature. The solventwas evaporated and the residue taken up in 400 ml of ethyl acetate, andwashed successively with 200 ml of water, 100 ml of 5% sodiumbicarbonate solution, 100 ml of 10% citric acid solution and 200 ml ofwater. The ethyl acetate solution was dried over anhydrous sodiumsulfate. Upon evaporation of the solvent, the residue was dissolved in20 ml of chloroform, and the solution was applied to a column (80 cm × 6cm) of 500 g of silica gel packed in chloroform. The product was elutedfirst with chloroform, and then 3% methanol-chloroform. The fractioneluted from 3% methanol-chloroform was evaporated to dryness to give25.8 g (63 percent) of N^(G) -nitro-N²-(tert-butoxycarbonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl esterin the form of a syrup. I.R. (KBr): 3,300 1,740, 1,690 cm⁻¹

(B) N^(G) -nitro-L-arginyl-N-(2-methoxyethyl)glycine ethyl esterhydrochloride

To a stirred solution of 29.8 g of N^(G) -nitro-N²-(tert-butoxycarbonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl esterin 50 ml of ethyl acetate was added 80 ml of 10% dry HCl-ethyl acetateat 0° C. After 3 hours, to this solution was added 200 ml of dry ethylether to precipitate a viscous oily product.

This was filtered and washed with dry ethyl ether to give 24.1 g ofN^(G) -nitro-L-arginyl-N-(2-methoxyethyl) glycine ethyl esterhydrochloride as an amorphous solid.

(C) N^(G) -nitro-N²-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycineethyl ester

To a stirred solution of 4.0 g of N^(G)-nitro-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester hydrochloride in20 ml of water and 20 ml of dioxane were added in turn 2.5 g of sodiumbicarbonate, and 3.5 g of 6,7-dimethoxy-2-naphthalenesulfonyl chloridein 30 ml of dioxane at 5° C, and stirring was continued for 3 hours atroom temperature. At the end of this period, the solvent was evaporatedand the residue dissolved in 40 ml of chloroform, and washed with 10 mlof 1N hydrochloric acid solution and 20 ml of water.

The chloroform solution was dried over anhydrous sodium sulfate. Uponevaporation of the solvent, the residue was chromatographed on 50 g ofsilica gel packed in chloroform, washed with chloroform and eluted with3% methanol-chloroform. The fraction eluted from 3% methanol-chloroformwas evaporated to give 5.3 g (87 percent) of N^(G) -nitro-N²-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycineethyl ester in the form of an amorphous solid. I.R. (KBr): 3,240, 1,740,1,630 cm⁻¹

(D) N²-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycineether ester:

To a solution of 3.00 g of N^(G) -nitro-N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester in50 ml of ethanol and 0.5 ml of acetic acid was added 0.5 g ofpalladium-black and then the mixture was shaken in a hydrogen atmospherefor 100 hours at room temperature. At the end of this period, theethanol solution was filtered to remove the catalyst and evaporated togive an oily product. Reprecipitation with ethanol-ethyl ether gave 2.53g (91%) of N²-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycineethyl ester.

For analysis of the product, a portion of the product was converted tothe flavianate; M.P. 185° C, I.R. (KBr): 3,375, 3,200, 1,740 cm⁻¹.

Analysis - Calcd. for C₂₅ H₃₇ N₅ O₈ S.C₁₀ H₆ N₂ O₈ S (percent): C,47.67; H, 4.92; N, 11.12 Found (percent): C, 47.64; H, 4.81; N, 11.12.

(E) N²-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine:

A solution of 2.5 g of N²-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycineethyl ester in 5 ml of ethanol and 7 ml of 1N sodium hydroxide solutionwas stirred for 30 hours at room temperature. At the end of this period,the solution was concentrated to 5 ml, chromatographed on 80 ml ofDaiaion .sup.® SK 102 ion exchange resin (200 - 300 mesh, H⁺ formmanufactured by Mitsubishi Chemical Industries Limited) packed in water,washed with water, and eluted with 3% ammonium hydroxide solution. Thefraction eluted from 3% ammonium hydroxide solution was evaporated todryness, and the residue was purified by reprecipitation withethanol-ethyl ether to give 1.32 g (72 percent) of N²-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycineas an amorphous solid. I.R. (KBr): 3,380, 3,180, 1,630 cm⁻¹

Analysis - Calcd. for C₂₃ H₃₃ N₅ O₈ S (percent): C, 51.20; H, 6.17; N,12.98 Found (percent): C, 50.93; H, 6.02; N, 12.63

The following compounds are prepared in a similar manner:

N²-(5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl-N-(2-ethoxyethyl)glycin

N²-(5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine

N² -(7-ethyl-2-naphthylsulfonyl)-L-arginyl-N-(2-metoxyethyl)glycine

N² -(5-methoxy-1-naphthylsulfonyl)-L-arginyl-N-cylcohexylglycine

N²-(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(3-cyclohexyl)propylgylcine

2- N²-(7-methyl-2-naphthylsulfonyl)-L-arginyl!-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid

2- N² -(7-methyl-2-naphthylsulfonyl)-L-arginyl!isoindoline-1-carboxylicacid

2- N²-(6,7-dimethyl-2-naphthylsulfonyl)-L-arginyl!isoindoline-1-carboxylicacid

2- N² -(2-naphthylsulfonyl)-L-arginyl!isoindoline-1-carboxylic acid

2- N²-(5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl!-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid

2- N²-(5,6,7,8-tetrahydro-1-naphthylsulfonyl)-L-arginyl!isoindoline-1-carboxylicacid

2- N²-(chloro-1-naphthylsulfonyl)-L-arginyl!-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid

1- N²-(5-hydroxy-1-naphthylsulfonyl)-L-arginyl!-1,2,3,4-tetrahydroquinoline-2-carboxylicacid

2- N²-(5-dimethylamino-1-naphthylsulfonyl)-L-arginyl!isoindoline-1-carboxylicacid

2- N²-(1-naphthylsulfonyl)-L-arginyl!-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid

EXAMPLE 4 (A) L-arginyl-N-(2-methoxyethyl)glycine ethyl esterhydrochloride

To a solution of 4.0 g of N^(G)-nitro-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester hydrochloride in50 ml of ethanol was added 0.5 g of palladium-black and then the mixturewas shaken in a hydrogen atmosphere for 150 hours at room temperature.At the end of this period, the ethanol solution was filtered to removethe catalyst and evaporated to give an oily product. Reprecipitationwith ethanol-ethyl ether gave 3.0 g (81%) ofL-arginyl-N-(2-methoxyethyl)glycine ethyl ester hydrochloride in theform of a powder.

(B) N²-(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycineethyl ester:

To a well stirred solution of 2.00 g ofL-arginyl-N-(2-methoxyethyl)glycine ethyl ester hydrochloride and 1.95 gof K₂ CO₃ in 20 ml of water and 10 ml of dioxane was added dropwise asolution of 2.17 g of 4,6-dimethoxy-2-naphthalenesulfonyl chloride in 30ml of dioxane over a period of 30 minutes while maintaining thetemperature at 0° C. The reaction mixing was stirred for an additional 5hours at room temperature. At the end of this period, the solvent wasevaporated and the residue taken up in 50 ml of chloroform. Thechloroform solution was filtered to remove the insoluble material anddried over anhydrous sodium sulfate. Addition of 150 ml of ethyl etherto the chloroform solution resulted in a precipitate which was separatedby decantation and purified by reprecipitation with ethanol-ethyl etherto give 2.31 g (72 percent) of N²-(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycineethyl ester.

For analysis of the product, a portion of the product was converted tothe flavianate; M.P. 225°-227° C. I.R. (KBr): 3,375, 3,200, 1,742 cm⁻¹.

Analysis - Calcd. for C₂₅ H₃₇ N₅ O₈ S.C₁₀ H₆ N₂ O₈ S (percent): C,47.67; H, 4.92; N, 11.12 Found (percent): C, 47.62; H, 4.84; N, 11.18

(B) N²-(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycineN²-(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycinewas obtained in the form of an amorphous solid in a manner similar tothat described in Example 3 (E). I.R. (KBr): 3,360, 3,180, 1,610 cm⁻¹.EXAMPLE 5 (A) N²-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-phenethylglycine

N^(G) -nitro-N²-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-phenethylglycine benzylester was prepared by the procedure described in Example 3, and has amelting point of 133°-5° C.

To a solution of 3.00 g of N^(G) -nitro-N²-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-phenethylgylcine benzylester in 50 ml of ethanol and 0.5 ml of acetic acid was added 0.5 g ofpalladium-black and then the mixture was shaken in a hydrogen atmospherefor 100 hours at room temperature. At the end of this period, theethanol solution was filtered to remove the catalyst and evaporated todryness. The residue was washed several times with dry ethyl ether andchromatographed on 80 ml of Daiaion ®SK 102 ion exchange resin (200 -300 mesh, H⁺ form, manufactured by Mitsubishi Chemical IndustriesLimited) packed in water, washed with water, and eluted with 3% ammoniumhydroxide solution. The fraction eluted from 3% ammonium hydroxidesolution was evaporated to dryness to give 1.71 g (70%) of N²-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-phenethylglycine as anamorphous solid.

I.R. (KBr): 3,360, 3,200, 1,590 cm⁻¹

Analysis - Calcd. for C₂₈ H₃₅ N₅ O₇ S (percent): C, 57.42; H, 6.02; N,11.97 Found (percent): C, 57.09; H, 6.06; N, 11.74

EXAMPLE 6 (A) N²-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycylchloride hydrochloride:

A suspension of 2.00 g of N²-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycinein 20 ml of thionyl chloride was stirred for 2 hours at roomtemperature. Addition of cold dry ethyl ether resulted in a precipitatewhich was collected by filtration and washed several times with dryethyl ether to give N²-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycylchloride hydrochloride.

(B) N²-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycinem-tolyl ester hydrochloride:

A mixture of 2.00 g of m-cresol and N²-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycylchloride hydrochloride obtained above was heated at 90° C for 50minutes. At the end of this period, the reaction mixture was cooled,washed several times with dry ethyl ether, and then dissolved in 10 mlof dry ethyl alcohol. Addition of cold dry ethyl ether resulted in aprecipitate which was washed several times with dry ethyl ether to give2.12 g (86 percent) of N²-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycinem-tolyl ester hydrochloride in the form of a powder.

I.R. (KBr): 3,250, 3,100, 1,740, 1,640 cm⁻¹.

The followng compounds are prepared in a similar manner:

N²-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-ethylthioethyl)glycinephenyl ester

N²-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-ethylthioethyl)glycinebenzyl ester

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-benzylglycine phenylester

N² -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-furfurylglycinebenzyl ester

N²-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycinephenyl ester

Phenyl 1- N²-(7-methyl-2-naphthylsulfonyl)-L-arginyl!-4-ethyl-2-piperidinecarboxylate

Benzyl 1- N²-(7-methyl-2-naphthylsulfonyl)-L-arginyl!-4-ethyl-2-piperidinecarboxylate

Benzyl 1- N²-(6-chloro-2-naphthylsulfonyl)-L-arginyl!-4-methyl-2-piperidinecarboxylate

Ethyl 4- N²-(7-methyl-2-naphthylsulfonyl)-L-arginyl!morpholine-3-carboxylate

Various other N² -arylsulfonyl-L-argininamides or salts thereof weresynthesized in accordance with the procedure of the above examples, andthe test results are summarized in Table 2.

EXAMPLE 7 Tablets Suitable For Oral Administration

Tablets containing the ingredients indicated below may be prepared byconventional techniques.

    ______________________________________                          Amount per tablet    Ingredient            (mg)    ______________________________________    N.sup.2 -(7-methoxy-2-naphthylsulfonyl)-                          250    L-arginyl-N-(2-methoxyethyl)glycine    Lactose               140    Corn starch           35    Talcum                20    Magnesium stearate    5    Total                 450       mg    ______________________________________

EXAMPLE 8 Capsules For Oral Administration

Capsules of the below were made up by thoroughly mixing together batchesof the ingredients and filling hard gelatin capsules with the mixture.

    ______________________________________                          Amount per capsule    Ingredient            (mg)    ______________________________________    N.sup.2 -(7-methoxy-2-naphthylsulfonyl)-                          250    L-arginyl-N-(2-methoxyethyl)glycine    Lactose               250    Total                 500       mg    ______________________________________

EXAMPLE 9 Sterile Solution For Infusion

The followng ingredients are dissolved in water for intravenousperfusion and the resulting solution is then sterilized.

    ______________________________________    Ingredients           Amount (g)    ______________________________________    N.sup.2 -(7-meythoxy-2-naphthylsulfonyl)-                          25    L-arginyl-N-(2-methoxyethyl)glycine    Buffer system         As desired    Glucose               25    Distilled water       500    ______________________________________

APPENDIX

There are now described in greater detail preparation of materials ofthe kind used in the foregoing examples.

PREPARATION A Arylsulfonyl chlorides (A) Sodium6,7-dimethoxy-2-naphthalenesulfonate

To a well stirred solution of 70.8 g of sodium6,7-dihydroxy-2-naphthalenesulfonate and 77.2 g of sodium hydroxide in450 ml of water was added dropwise 230 ml of dimethyl sulfate at 60° Cover a period of one hour, during which the product precipitated. Tothis reaction mixture was added in portions 38.8 g of sodium hydroxide,and stirring was continued for 1 hour. After one hour at roomtemperature, the precipitate was filtered, washed with ethanol and driedto give 50 g of sodium 6,7-dimethoxy-2-naphthalenesulfonate.

(B) 6,7-dimethoxy-2-naphthalenesulfonyl chloride

To a stirred suspension of 50 g of finely divided sodium6,7-dimethoxy-2-naphthalenesulfonate in 100 ml of dimethylformamide wasadded dropwise 62.2 ml of thionyl chloride at room temperature. After 30minutes, the reaction mixture was poured into 1 l of ice water, and theprecipitate filtered and then dissolved into 250 ml of benzene. Thebenzene solution was repeatedly washed with water and dried overanhydrous sodium sulfate. The solvent was evaporated to dryness invacuo, and the residue was recrystallized from benzene-n-hexane (1 : 1)to give 32 g of 6,7-dimethoxy-2-naphthalenesulfonyl chloride, M.P.127.5°-129.5° C.

Analysis - Calcd. for C₁₂ H₁₁ O₄ SCl (percent): C, 50.26; H, 3.87; Cl,12.37 Found (percent): C, 50.45; H, 4.00; Cl, 12.33

The following arylsulfonyl chlorides not previously reported in thechemical literature were synthesized by the aforementioned procedurewhich is essentially that as described in E.H. Rodd, "Chemistry ofCarbon Compounds", Elsevier Publishing Company, 1954, Vol III, P.441-469.

    ______________________________________    No.  Arylsulfonyl Chloride    M.P. (° C)    ______________________________________          ##STR745##              118-119.5    2          ##STR746##              136.5-138.5    3          ##STR747##              137-139    ______________________________________

PREPARATION B Amino acid derivatives (A) N-butylglycine tert-butyl ester

To 36.5 g of butylamine was added with stirring 15.05 g of tert-butylchloroacetate over a period of 30 minutes, while maintaining thetemperature at 30°-70° C. The reaction mixture was held at 70° C for anadditional 1 hour. At the end of this period, the excess butyl amine wasevaporated in vacuo, and the residue was taken up in 40 ml of 2N NaOHsolution and 50 ml of benzene, transferred into a separatory funnel andwell shaken. The benzene solution was separated, washed with water,dried over anhydrous sodium sulfate and filtered. After evaporation ofbenzene, the residue was distilled under reduced pressure to give 17.0 g(90.9 percent) of N-butylglycine tert-butyl ester, B.P. 76°C/4 mmHg.

The following amino acid tert-butyl esters not previously reported inthe chemical literature were synthesized by the aforementioned procedurewhich is essentially that as taught by A. J. Speziale et al., J. Org.Chem. 25 731 (1960).

    ______________________________________    No.  Amino Acid Derivative                              B.P.    ______________________________________          ##STR748##        95° C/20 mmHg    2          ##STR749##        65° C/5 mmHg    3          ##STR750##        89-90° C/2.5 mmHg    4          ##STR751##        83-5° C/1.5 mmHg    5          ##STR752##        125-130° C/4 mmHg    6          ##STR753##        61-2° C/2 mmHg    7          ##STR754##        94° C/3 mmHg    8          ##STR755##        60-3° C/3 mmHg    9          ##STR756##        95-7° C/5 mmHg    10          ##STR757##        102° C/4 mmHg    11          ##STR758##        166° C/10 mmHg    12          ##STR759##        106-9° C/1.5 mmHg    13          ##STR760##        97° C/2.5 mmHg    14          ##STR761##        101° C/5 mmHg    15          ##STR762##        101° C/5 mmHg    16          ##STR763##        105° C/4 mmHg    17          ##STR764##        129-130° C/8 mmHg    18          ##STR765##        145° C/15 mmHg    19          ##STR766##        156° C/10 mmHg    20          ##STR767##        93° C/26 mmHg    21          ##STR768##        110° C/27 mmHg    22          ##STR769##        124° C/26 mmHg    23          ##STR770##        88-90° C/6 mmHg    24          ##STR771##        116-8° C/2 mmHg    25          ##STR772##        167° C/16 mmHg    26          ##STR773##        125° C/16 mmHg    27          ##STR774##        141° C/15 mmHg    28          ##STR775##        89° C/3 mmHg    29          ##STR776##        111° C/1 mmHg    30          ##STR777##        91-2° C/1 mmHg    31          ##STR778##        115° C/2 mmHg    32          ##STR779##        82-84° C/2 mmHg    33          ##STR780##        150° C/0.5 mmHg    34          ##STR781##        95-6° C/2 mmHg    35          ##STR782##    ______________________________________

(B) N-(2-methoxyethyl)glycine ethyl ester

To a stirred solution of 165.2 g of 2-methoxyethylamine and 202.4 g oftriethylamine in 1 l of benzene was added dropwise a solution of 334.0 gof ethyl bromoacetate in 200 ml of benzene in one hour at roomtemperature. At the end of this period, the mixture was heated at refluxfor 2 hours to complete the reaction. Upon chilling, the triethylaminehydrobromide was removed by filtration and washed with benzene. Afterremoval of the solvent, the product was distilled in vacuo to yield242.8 g (75.3 percent) of N-(2-methoxyethyl)glycine ethyl ester, B.P.73°-5° C/4 mmHg.

The following amino acid ethyl esters not previously reported in thechemical literature were synthesized by the aforementioned procedurewhich is essentially that as taught by A. J. Speziale et al., J. Org.Chem., 25 731 (1960).

    ______________________________________                            M.P. (° C) or B.P.    No.  Amino Acid Ethyl Ester                            (° C/mmHg)    ______________________________________          ##STR783##        57-8° C/3 mmHg    2          ##STR784##        63-4° C/3 mmHg    3          ##STR785##        91-3° C/2 mmHg    4          ##STR786##        101-2° C    5          ##STR787##        113-6° C/3 mmHg    6          ##STR788##        116-7° C/1 mmHg    7          ##STR789##        78-80° C/2 mmHg    8          ##STR790##        63-4° C    ______________________________________

(C) N-(2-methoxyethyl)glycine benzyl ester p-toluenesulfonate

To a solution of 55.8 g of N-(2-methoxyethyl)glycine tert-butyl ester in200 ml of benzene was added 63.8 g of benzyl alcohol and 72.9 ofp-toluenesulfonic acid monohydrate. The mixture was heated at reflux for10 hours with the continuous removal of water through a Dean-Stark watertrap. At the end of this period, the solution was concentrated in vacuo,and to the residue was added 300 ml of dry ethyl ether. After 2 hours atroom temperature, the formed precipitate was filtered, washed with dryethyl ether and then recrystallized from ethyl acetate to yield 99.2 g(85 percent) of N-(2-methoxyethyl)glycine benzyl esterp-toluenesulfonate, M.P. 95°-6° C.

The followng amino acid benzyl ester p-toluenesulfonate not previouslyreported in the chemical literature were synthesized by theaforementioned procedure.

    ______________________________________            Amino Acid Benzyl Ester    No.     p-Toluenesulfonate    M.P. (° C)    ______________________________________             ##STR791##            97-9    2             ##STR792##           122-4    3             ##STR793##            94-5    4             ##STR794##            66-8    5             ##STR795##           101-2    6             ##STR796##           140-3    7             ##STR797##           154-6    8             ##STR798##           133-5    9             ##STR799##           133-5    10             ##STR800##           133-8    11             ##STR801##           103-6    12             ##STR802##            92-4    13             ##STR803##           123-6    14             ##STR804##           119-123    15             ##STR805##           130-1    ______________________________________

PREPARATION C 2-Piperidinecarboxylic acids and esters thereof (A)4-methyl-2-piperidinecarbonitrile

To 500 g of 10% sodium hypochlorite solution cooled in an ice bath,there was added dropwise a solution of 33.6 g (0.21 mole) of4-methylpiperidine acetate in 10 ml of water over a period of 1 hour. Atthe end of this period, the reaction product was extracted twice with500 ml of ethyl ether and dried over anhydrous sodium sulfate. Afterevaporation of ethyl ether, the residue was added dropwise to a solutionof 11.8 g (0.21 mole) of potassium hydroxide in 100mls of 96% ethanolunder reflux Refluxing was continued for an additional 10 minutes.Ethanol was evaporated, and the residue was dissolved into 50 ml of 2Nsodium hydroxide solution and then extracted with ether.

The ether layer was dried over anhydrous sodium sulfate and then etherevaporated. The residue was added to an ice-cooled solution of 27 g (1mole) of hydrogen cyanide and 25 ml of concentrated hydrochloric acid in300 ml of water. The solution was stirred at a temperature of 10 to 20°C for 4 hours and thereafter made basic by the addition of solid sodiumhydroxide. The reaction product was extracted with ether, dried overanhydrous sodium sulfate and then distilled under reduced pressure togive 17 g (66%) of 4-methyl-2-piperidinecarbonitrile, B.P. 96°-97° C/10mmHg.

The following 2-piperidinecarbonitriles not previously reported in thechemical literature were synthesized by the aforementioned procedurewhich is essentially that as taught by Grundon et al., J. Chem. Soc.,1963, 3898, Grundon et al., J. Chem. Soc., 1964, 2448, R. Bonnett etal., J. Chem. Soc., 1959, 2092 and H. Bohme et al., Ber., 92 1613(1959).

    ______________________________________     ##STR806##    No.        R.sub.7          B.P.    ______________________________________    1        4-CH.sub.2 CH.sub.3                              105-106° C/9 mmHg.    2        4-CH.sub.2 CH.sub.2 CH.sub.3                              116° C/8 mmHg.              ##STR807##      104° C/4 mmHg.    4        2-CH.sub.3    ______________________________________

(B) 4-Methyl-2-piperidinecarboxylic acid hydrochloride

A solution of 16 g of 4-methyl-2-piperidinecarbonitrile in 250 ml of 6Nhydrochloric acid was refluxed for 6 hours. After evaporation of thesolvent, the residue was recrystallized from water to give 13 g of4-methyl-2-piperidinecarboxylic acid hydrochloride.

(C) Ethyl 4-methyl-2-piperidinecarboxylate

A solution of 13 g (0.072 mole) of 4-methyl-2-piperidinecarboxylic acidhydrochloride and 50 ml of thionyl chloride in 300 ml of ethanol wasrefluxed for 4 hours. At the end of this period, the solvent wasevaporated under reduced pressure, and the residue was extracted with asolution of chloroform and saturated potassium carbonate solution.

The chloroform layer was dried over anhydrous sodium sulfate and thenchloroform was evaporated. Distillation of the residue gave 7.4 g (60%)of ethyl 4-methyl-2-piperidinecarboxylate, B.P. 76°-77° C/3 mmHg.

(D) Benzyl 4-methyl-2-piperidinecarboxylate p-toluenesulfonate

A solution of 20 g (0.112 mole) of 4-methyl-2-piperidinecarboxylic acidhydrochloride, 24 g (0.224 mole) of benzyl alcohol and 25.6 g (0.134mole) of p-toluenesulfonic acid monohydrate in 100 ml of benzene wasrefluxed for 5 hours with the continuous removal of water through aDean-Stark water trap. At the end of this period, the solvent wasdistilled off, and the residue was washed with ether-n-hexane andrecrystallized to give 10 g (22%) of benzyl4-methyl-2-piperidinecarboxylate p-toluenesulfonate, M.P. 160°-163° C.

The following 2-piperidinecarboxylates not previously reported in thechemical literature were synthesized by the aforementioned procedure.

    ______________________________________     ##STR808##                       Addition    No.      R.sub.7   moiety     B.P.    ______________________________________    1      4-CH.sub.2 CH.sub.3                       --         82-4° C/3.5 mmHg    2      4-CH.sub.2 CH.sub.2 CH.sub.3                       HCl            ##STR809## --         95-6° C/2 mmHg    4      2-CH.sub.3  --         57° C/3 mmHg    ______________________________________

Morpholine-3-carboxylic acid hydrochloride was prepared by the proceduredescribed above, and has a melting point of 200°-2° C.

The following starting materials for the preparation of the N²-arylsulfonyl-L-argininamides were prepared by the procedures describedin the following literatures:

    ______________________________________    Compound        Literature    ______________________________________     ##STR810##     J. Org. Chem., 29 2203 (1964)     ##STR811##     J. Org. Chem., 29 2203 (1964)     ##STR812##     J. Am. Chem. Soc., 59 200 (1937)     ##STR813##     Zh. Obshch. Khim., 9 2245 (1973)     ##STR814##     Ber., 44 2034 (1911)     ##STR815##     Ber., 65 927 (1932)    ______________________________________

The methyl or ethyl ester of the aforementioned compounds were preparedby a conventional esterification procedure. Ethylthiomorpholine-3-carboxylate has a boiling point of 108° C/4 mmHg.

Diethyl piperidine-2,6-dicarboxylate hydrochloride was prepared by theconventional esterification of piperidine-2,6-dicarboxylic acid and hasa melting point of 184°-6° C. Isoindoline-1-carboxylic acid was preparedby a procedure similar to that for the preparation ofisoquinoline-3-carboxylic acid described in Ber., 44 2034 (1911). Ethylisoindoline-1-carboxylate hydrochloride was prepared by the conventionalesterification of isoindoline-1-carboxylic acid and has a melting pointof 139°-140.5° C. Having now fully described the invention, it will beapparent to one of ordinary skill in the art that many changes andmodifications can be made thereto without departing from the spirit ofthe invention as set forth herein.

What is claimed as new and desired to be secured by letters patent ofthe United States is:
 1. An N² -arylsulfonyl-L-argininamide having theformula (I): ##STR816## or a pharmaceutically acceptable salt thereof,wherein R is ##STR817## wherein R₁ is --COOR₃ wherein R₃ is hydrogen, C₁-C₁₀ alkyl, C₆ -C₁₀ aryl, C₇ -C₁₂ aralkyl or 5-indanyl; each R₂independently is hydrogen, C₁ -C₁₀ alkyl, phenyl, C₁ -C₅ alkoxy, C₂ -C₆alkoxycarbonyl or carboxy; n is an integer of 1 to 4, R₁ is substitutedinto the piperidine ring at the 2 or 3-position; and R₂ is substitutedinto the piperidine ring at the 2, 3, 4, 5 or 6-position; and Ar is 5,6, 7, 8-tetrahydronaphthyl or naphthyl each of which is optionallysubstituted with at least one substituent selected from the groupconsisting of halo, hydroxy, nitro, cyano and C₁ -C₁₀ alkyl.
 2. Thecompound of claim 1 wherein R₂ is hydrogen, C₁ -C₅ alkyl or C₁ -C₅alkoxy.
 3. The compound of claim 1, wherein R₁ is substituted into thepiperidine ring at the 2 position.
 4. A pharmaceutical composition whichcomprises an antithrombotically effective amount of a compound of claim1 and a pharmaceutically acceptable carrier.
 5. A method of inhibitingactivity and suppressing activation of thrombin in vivo which comprisesadministering to a mammal a pharmaceutical effective amount of acompound of claim 1.